ES2334843T3 - THROMBOPOYETINE MIMETICS. - Google Patents

Abstract

A compound having Formula (VI): ** (See formula) ** in which: R is a substituted aryl; and R1 is hydrogen; or: R is hydrogen; and R1 is a substituted aryl; and in any case: R2 and R3 are each independently selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphic acid and acid sulfonic; R15 is selected from the group consisting of alkyl, substituted alkyl, C1-C12 aryl, alkoxy and halogen; m is 0-4; and Y is selected from: phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl are optionally substituted with one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C1-C12 aryl, substituted C1-C12 aryl, alkoxy and halogen; and where: by the term aryl, as used herein, is meant a cyclic or polycyclic aromatic ring containing from 1 to 14 carbon atoms and optionally containing from one to five heteroatoms, with the proviso that when the number of carbon atoms is 1 the aromatic ring contains at least four heteroatoms, when the number of carbon atoms is 2 the aromatic ring contains at least three heteroatoms, when the number of carbons is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom; by the term aryl C1-C12, as used herein, is understood to mean phenyl, naphthalene, 3,4-methylenedioxyphenyl, pyridine, biphenyl, quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole or tetrazole; and by the substituted term, as used herein, it is understood that the subject chemical moiety has one or more substituents selected from the group consisting of: -CO2R20, aryl, -C (O) NHS (O) 2R20, -NHS (O) 2R20, hydroxyalkyl, alkoxy, -C (O) NR21R22, acyloxy, alkyl, amino, N-acylamino, hydroxy, - (CH2) gC (O) OR8, -S (O) nR8, nitro, tetrazole, cyano , oxo, halogen, and trifluoromethyl, where g is 0-6, R8 is hydrogen or alkyl, R20 is selected from hydrogen, C1-C4 alkyl, aryl and trifluoromethyl, and R21 and R22 are independently selected from hydrogen, C1-C4 alkyl , aryl and trifluoromethyl, and n is 0-2; and pharmaceutically acceptable salts, hydrates and solvates thereof.

Description

Mimetics of thrombopoietin.

Field of the Invention

The present invention relates to mimetics of thrombopoietin (TPO) and its use as promoters of thrombopoiesis and megakaryocytopoiesis.

Background of the invention

Megakaryocytes are cells derived from the bone marrow, which are responsible for platelet production circulating blood Although they comprise <0.25% of the cells of the bone marrow in most species, have> 10 times the volume of typical spinal cells. See Kuter and cabbage. Proc. Natl Acad. Aci. USA 91: 11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis through which they replicate their nuclei but fail at experience cell division and therefore give rise to cells polyploids In response to a reduced platelet count, endomitotic ratio increases, megakaryocytes form less ploidy and the number of megakaryocytes increases up to 3 times. See Harker J. Clin. Invest. 47: 458-465 (1968). On the contrary, in response to a high platelet level, the endomitotic proportion decreases, megakaryocytes of lower ploidy and the number of megakaryocytes may decrease by fifty%.

The exact mechanism of physiological feedback by which platelet mass circulating regulates the endomitotic proportion and the number of medullary megakaryocytes. It is currently believed that the factor circulating thrombopoietic involved in the mediation of this loop of Feedback is thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral regulator in situations that involve thrombocytopenia. See, for example, Metcalf Nature 369: 519-520 (1994). Has been shown in several studies that TPO increases platelet count, increases platelet size and increases the incorporation of isotopes in platelets of recipient animals. Specifically, it believes that TPO affects megakaryocytopoiesis in several ways: (1) produces increases in the size and number of megakaryocytes (2) produces an increase in DNA content, in the form of polyploidy, in megakaryocytes (3) increases the endomitosis of megakaryocytes (4) produces greater maturation of megakaryocytes; and (5) produces a increase in the percentage of precursor cells, in the form of small acetylcholinesterase positive cells, in the bone marrow. Because platelets (thrombocytes) are necessary for blood coagulation and when its members are very few a patient is at risk of death from catastrophic hemorrhage, TPO it has a potential useful application both in diagnosis and in the treatment of various hematological disorders, for example, diseases mainly due to platelet defects (see Harker et al. Blood 91: 4427-4433 (1998)). Ongoing clinical trials with TPO have indicated that TPO can administered safely to patients (see Basser et al. Blood 89: 3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336: 404-409 (1997)). In addition, studies  recent have provided a basis for the projection of the efficacy of TPO therapy in the treatment of thrombocytopenia, and resulting in particularly thrombocytopenia caused by chemotherapy, radiation therapy or bone marrow transplant as a treatment for cancer or lymphoma. (See Harker, Curr. Opin. Hematol. 6: 127-134 (1999)).

The gene encoding TPO has been cloned and characterized. See Kuter et al., Proc. Natl Acad. Sci. USA 91: 11104-11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al., Nature 369: 571-574 (1994); and Sauvage et al., Nature 369: 533-538 (1994). Thrombopoietin is a glycoprotein with at least two forms, with apparent molecular masses of 25 kDa and 31 kDa, with a common N-terminal amino acid sequence. See Baatout, Haemostasis 27: 1-8 (1997); Kaushansky, New Engl. J. Med. 339: 746-754 (1998). Thrombopoietin appears to have two distinct regions separated by a potential Arg-Arg cleavage site. The amino-terminal region is highly conserved in humans and mice, and has some homology with erythropo-
yetina and interferon-? and interferon-?. The carboxy-terminal region shows a wide divergence between species.

The DNA sequences and the peptide sequences encoded for the human TPO receptor (TPO-R; also known as c-mpl). (See Vigon et al. Proc. Natl. Acad. Sci. USA 89: 5640-5644 (1992)). TPO-R is a member of the growth factor receptor family of hematopoietin, a family characterized by a structural design common extracellular domain, including for C residues preserved in the N-terminal portion and a motive WSXWS near the transmembrane region. (See Bazan Proc. Natl. Acad. Sci. USA 87: 6934-6938 (1990)). The test of that this receptor plays a functional role in hematopoiesis includes observations that its expression is restricted to the spleen, Bone marrow or fetal liver in mice (see Souyri et al. Cell 63: 1137-1147 (1990)) and megakaryocytes, platelets and CD34 + cells in humans (see Metia et al. Blood 82: 1395-1401 (1993)). Another proof that TPO-R is a key regulator of megakaryopoiesis is the fact that the exposure of CD34 + cells to synthetic antisense oligonucleotides for RNA from TPO-R selectively inhibits the appearance of colonies of megakaryocytes without affecting the formation of erythroid colonies or myeloids. Some workers postulate that the receiver works as a homodimer, similar to the situation with receptors for G-CSF and erythropoietin. (see Alexander et al. EMBO J. 14: 5569-5578 (1995)).

The slow recovery of levels platelets in patients suffering from thrombocytopenia is a problem  serious, and the search for an agonist of the blood growth factor capable of accelerating regeneration platelet (see Kuter, Seminars in Hematology, 37: Supp 4: 41-49 (2000)).

It would be desirable to provide compounds that allow thrombocytopenia treatment by acting as a TPO mimetic.

As described in this document, it has been unexpectedly discovered that certain derivatives of hydroxy-l-azobenzene are effective as TPO receptor agonists, and that are potent mimetics of TPO

Summary of the invention

The present invention relates to compounds of Formula (VI):

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one

in the that:

quad

R is a substituted aryl; and R1 is hydrogen;

or:

quad

R is hydrogen; and R1 is an aryl replaced;

and in each case:

quad

each of R 2 and R 3 of is selected independently between hydrogen, alkyl C 1-6, C 1-6 alkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphic acid and acid sulfonic;

quad

R 15 is selected from the constituted group by alkyl, substituted alkyl, aryl C 1 -C 12, alkoxy and halogen;

quad

m is 0-4; and

quad

And it is selected from:

phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl are optionally substituted with one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, aryl C 1 -C 12 substituted, alkoxy and halogen;

and pharmaceutically active salts, hydrates and solvates Acceptable of them.

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These compounds are within the scope of the Reference Formula (I):

2

in the that:

each of R, R1, R2 and R3 is independently select from hydrogen, alkyl C 1-6, - (CH 2) p OR 4, -C (O) OR 4, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S (O) n R 4, cycloalkyl, -NR 5 R 6, -OH protected, -CONR 5 R 6, phosphonic acid, acid sulfonic acid, phosphonic acid, -SO 2 NR 5 R 6 and a heterocyclic methylene substituent as depicted in the Formula (III),

3

in the that,

p is 0-6,

n is 0-2,

each of V, W, X and Z are independently selected from O, S and NR 16, where R 16 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, alkyl substituted, substituted cycloalkyl and aryl C 1 -C 12 substituted, R 4 is selected Among: hydrogen, alkyl, cycloalkyl, aryl C 1 -C 12, substituted alkyl, cycloalkyl substituted and C 1 -C 12 substituted aryl Y

each one of R 5 and R 6 is independently selected from hydrogen, alkyl, substituted alkyl, C 3-6 cycloalkyl and arilo,

or R 5 and R 6 taken together with the nitrogen to which they are attached they represent a saturated ring of 5 to 6 members that contains up to a different heteroatom selected from oxygen and nitrogen;

quad

m is 0-6; Y

quad

AR is a cyclic or polycyclic aromatic ring that it contains 3 to 16 carbon atoms and optionally it contains one or more heteroatoms, with the proviso that when the number of carbon atoms be 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the ring aromatic contains at least one heteroatom and is optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, cycloalkyl substituted, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C (O) OR 4, -C (O) NR 10 R 11, S (O) 2 NR 10 R 11, -S (O) n R 4 and -OH protected,

quad

where n is 0-2,

quad

R 4 is hydrogen, alkyl, cycloalkyl, aryl C 1 -C 12, substituted alkyl, cycloalkyl substituted and substituted C 1 -C 12 aryl, Y

quad

R 10 and R 11 are independently hydrogen, cycloalkyl, C 1 -C 12 aryl, substituted cycloalkyl, C 1 -C 12 aryl substituted, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C (O) OR 4, -S (O) n R 4, -C (O) NR 4 R 4, -S (O) 2 NR 4 R 4, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, aryl substituted and -OH protected,

quad

or R 10 and R 11 taken together with the nitrogen to which they are attached represent a saturated ring from 5 to 6 members containing up to a different heteroatom selected between oxygen and nitrogen,

quad

where R 4 is as described above and n is 0-2;

and salts, hydrates, solvates and esters pharmaceutically acceptable thereof;

with the proviso that at least one of R, R 1, R 2 and R 3 is a substituted aryl group or a heterocyclic methylene substituent as depicted in the Formula (III)

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The present invention relates to the use of a compound of Formula (VI) in the preparation of a medicament for treat thrombocytopenia

The present invention also relates to discovery that the compounds of Formula (VI) are active as agonists of the TPO receptor.

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In a further aspect of the invention it is provided new procedures and new intermediates useful for preparing TPO mimetic compounds of the present invention.

They are included in the present invention pharmaceutical compositions comprising a pharmaceutical vehicle and compounds useful in the processes of the invention.

They are also included in the present invention procedures to co-administer the compounds TPO mimetics of the present invention with more ingredients assets.

Detailed description of the invention

The present invention relates to compounds of Formula (VI) as described above.

The compounds of Formula (VI) of the present invention are within the scope of the Reference Formula (II):

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4

in the that:

quad

each of R, R1, R2 and R3 is independently select from hydrogen, alkyl C 1-6, - (CH 2) p OR 4, -C (O) OR 4, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S (O) n R 4, cycloalkyl, -NR 5 R 6, -OH protected, -CONR 5 R 6, phosphonic acid, acid sulfonic acid, phosphonic acid, -SO 2 NR 5 R 6 and a heterocyclic methylene substituent as represented by the Formula (III),

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5

in the that

p is 0-6,

n is 0-2

each of V, W, X and Z are independently selected from O, S and NR 16, where R 16 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, alkyl substituted, substituted cycloalkyl and aryl C 1 -C 12 substituted,

R 4 is hydrogen, alkyl, cycloalkyl, aryl C 1 -C 12, substituted alkyl, cycloalkyl substituted and aryl C 1 -C 12 replaced,

Y

each one of R 5 and R 6 is independently selected from hydrogen, alkyl, substituted alkyl, C 3-6 cycloalkyl and arilo,

or R 5 and R 6 taken together with the nitrogen to which they are attached they represent a saturated ring of 5 to 6 members that contains up to a heteroatom more selected between oxygen and nitrogen;

quad

R 15 is selected from the constituted group by alkyl, C 1 -C 12 aryl, hydroxy, alkoxy, substituted alkyl, C 1 -C 12 aryl substituted and halogen;

quad

m is 0-6; and

quad

And it is selected from alkyl, substituted alkyl and a cyclic or polycyclic aromatic ring containing from 3 to 14 carbon atoms and optionally containing one to three heteroatoms, with the proviso that when the number of atoms of carbon be 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contain at least one heteroatom, and optionally substituted with one or more substituents selected from the group constituted by: alkyl, substituted alkyl, aryl C 1 -C 12, substituted cycloalkyl, aryl C 1 -C 12 substituted, hydroxy, aryloxy, alkoxy, cycloalkyl, nitro, cyano, halogen and -OH protected;

and salts, hydrates, solvates and esters pharmaceutically acceptable thereof;

with the proviso that at least one of R, R 1, R 2 and R 3 is a substituted aryl group or a heterocyclic methylene substituent as depicted in the Formula (III)

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Among the compounds of Reference Formula (II) of the present invention include compounds in which R 15 is not alkoxy.

Among the compounds of Reference Formula (II) of the present invention include those having the Formula (SAW):

6

in the that:

R is a substituted aryl; and R1 is hydrogen;

or:

R is hydrogen; and R1 is an aryl replaced; and in any case:

quad

each of R2 and R3 is selected independently between hydrogen, alkyl C 1-6, C 1-6 alkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphic acid and acid sulfonic;

quad

is selected from the group consisting of alkyl, substituted alkyl, C 1-12 aryl, alkoxy and halogen;

quad

m is 0-4; and

quad

And you select between,

phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl are optionally substituted with one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, aryl C 1 -C 12 substituted, alkoxy and halogen;

and salts, hydrates, solvates and esters pharmaceutically acceptable thereof.

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Among the compounds of Formula VI of the present invention is particularly preferred those in the that,

quad

R is a C 1 -C 12 aryl replaced;

quad

Y

quad

R1 is hydrogen;

quad

each of R2 and R3 is selected independently between hydrogen, alkyl C 1-6, C 1-6 alkoxy, nitro, cyano, halogen, substituted alkyl and cycloalkyl;

quad

R 15 is selected from the constituted group by alkyl, substituted alkyl, aryl C 1 -C 12, alkoxy and halogen;

quad

m is 0-2; and

quad

And is selected from, phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl are optionally substituted with one to three substituents selected among the group consisting of: alkyl, substituted alkyl, aryl C 1 -C 12, aryl C 1 -C 12 substituted, alkoxy and halogen;

and salts, hydrates, solvates and esters pharmaceutically acceptable thereof.

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The most preferred compounds of Formula VI of the present invention are those in which,

quad

R is a substituted phenyl or pyridinyl ring; Y

quad

R1 is hydrogen;

quad

each of R2 and R3 is selected independently between hydrogen, alkyl C 1-6, substituted alkyl and halogen;

quad

R 15 is selected from the constituted group by C 1-4 alkyl, alkoxy C 1-4, aryl C 1 -C 12 and halogen;

quad

m is 0; and

quad

And you select between,

quad

phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl is optionally substituted with one to three substituents selected from the group consisting of: alkyl, substituted alkyl, aryl C 1 -C 12, aryl C 1 -C 12 substituted, alkoxy and halogen;

and salts, hydrates, solvates and esters pharmaceutically acceptable thereof.

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Among the compounds of the present invention are prefer:

Acid 4 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-4-carboxylic acid;

Acid 4 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3 '- {N' - [1- (4- tert- Butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

2-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino acid -5'-chloro-2 acid '-hydroxy-biphenyl-3-carboxylic acid;

2-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 acid -carboxylic;

3-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5 acid -carboxylic;

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Acid 2-aza-5'-chloro-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2 ' -hydroxybiphenyl-3-carboxylic acid;

2-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 acid '-methyl-biphenyl-3-carboxylic acid;

Acid 2-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 ' -methylbiphenyl-3-carboxylic acid;

3 '- {N' - [1- (4- tert- Butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5'-methylbiphenyl- 3-carboxylic;

3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino } -5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid;

Acid 7 - ({N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxyphenyl) quinolin-4 [1H] - one-3-carboxylic;

7 - ({N '- [1- (4- tert- Butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxyphenyl) quinolin-4 [1H] acid -one-3-carboxylic;

Acid 3-Aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- carboxylic;

Acid 3-aza-3 '- (N' - [1- {3-methyl- [4- (1-methyl ethyl) phenyl] -5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino) -2'- hydroxybiphenyl-5-carboxylic;

3-aza-3 '- {N' - [1- (4- tert- butylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- acid carboxylic;

Acid 5'-chloro-3 '- {N' - [1 '- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-carboxylic;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3,5-dioxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (2-ethoxy-2-oxoethyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-4' - (tetrazol-5- il) biphenyl;

3 '- (N' - {1- [2- (N- tert- butyl) amino-2-oxoethyl] -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino acid) -2 '-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [3-Chloro-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

5-chloro-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-4' - ( tetrazol-5-yl) biphenyl;

Acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,5-dicarboxylic acid;

Acid 3-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 ' -methylbiphenyl-5-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-4-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (4-methoxyphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

(3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-biphenyl) -1 , 1,1, -trifluoromethanesulfonamide;

Acid 3 '- {N' - [1- (3,4-dichlorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [3-methyl-5-oxo-1- (3-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 8- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} quinolin-4 [1 H] -one-3-carboxylic acid;

Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-N-methylcarboxamidolfenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

N- [1- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-yl) methanoyl] methanesulfonamide;

Acid 3 '- {N' - [3-methyl-5-oxo-1-phenyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [3-methyl-1- (4-methylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (4-chlorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethoxy) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic;

3 '- {N' - [3- tert- Butyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid ;

Acid 3 '- {N' - [3-methyl-1- (4-methyl-2,3,5,6-tetrafluorophenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'- hydroxy-biphenyl-3-carboxylic;

Acid 3 '- {N' - [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-phenyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -5-oxo-3-phenyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

3- {N '- [1- (3,4-dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino-2-hydroxy-3'-tetrazol-5-yl- biphenyl;

3- {N '- [1- (3,4-dimethylphenyl) -3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

3- {N '- [1- (3,4-dimethylphenyl) -3- (1-methylethoxy) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl;

3- {N '- [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl;

3- {N '- [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5 -ylbiphenyl;

3- {N '- [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic;

3- {N '- [1- (3,4-dimethylphenyl) -3-pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl;

3- {N '- [1- (3,4-dimethylphenyl) -3-pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic;

3- {N '- [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5 -ylbiphenyl;

Acid 3 '- {N' - [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylpyrimidin-2-yl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3'-N- tert- butoxycarbonylamino-3- {N '- [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxybiphenyl ;

3'-amino-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxybiphenyl;

3- {N '- [1- (3-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl;

Acid 3 '- {N' - [1- (3-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [3-methyl-5-oxo-1- (2,3,4,5,6-pentafluorophenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3' -tetrazol-5-ylbiphenyl;

Acid 3 '- {N' - [3-methyl-5-oxo-1- (2,3,4,5,6-pentafluorophenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-carboxylic;

Acid 3 '- {N' - [1- (3,4-Difluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

3- {N '- [1- (3,4-Difluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-trifluoromethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -6-fluoro-2'-hydroxybiphenyl-3- carboxylic;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methyl-1 H -pyrrole-3-yl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3- (1-methyl-1H-pyrrol-3-yl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} - 2-hydroxy-3'-tetrazol-5-ylbiphenyl;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic;

3- {N '- [1- (3,4-dimethylphenyl) -3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl;

N- (2'-hydroxy-3 '- {N'-1'3-methyl-5-oxo-1- (4-trifluoromethyl-phenyl) -1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl -3-yl) -1,1,1-trifluoromethanesulfonamide;

N- (2'-hydroxy-3 '- {N' - [1- (3-fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl-3-yl) -1,1,1-trifluoromethanesulfonamide;

N- (2'-hydroxy-3 '- {N' - [1- (4-fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl-3-yl) -1,1,1-trifluoromethanesulfonamide;

N- (2'-hydroxy-3 '- {N' - [1- (3,4-difluorophenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl-3-yl) -1,1,1-trifluoromethanesulfonamide;

N- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-yl ) guanidine;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thien-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic;

Acid 3 '- {N' - [3-cyclopropyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiazol-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic;

Acid 3 '- {N' - [3- (benzyloxymethyl) -1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [3-ethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-hydroxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [3-benzyloxymethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methylsulfanylmethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic;

Acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-methylsulfanylmethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

N- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -yl) methanesulfonamide;

Acid 3 '- [N' - (1-benzo [1,3] dioxol-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene) hydrazino] -2'-hydroxybiphenyl-3- carboxylic;

Acid 3 '- {N' - [1- (3,5-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -4'-hydroxybiphenyl-4-carboxylic acid;

Acid 3 '- {N' - [1- (3-Chloro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -4'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-phosphonic;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,4-dicarboxylic acid;

Acid 2 ', 6-dihydroxy-3' - {N '[1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} biphenyl-3-carboxylic acid;

Acid 4-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- carboxylic;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-sulfonic acid;  Y

5- (3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-ylmethylene ) thiazolidine-2,4-dione;

and, hydrates, solvates and esters salts pharmaceutically acceptable thereof.

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The compounds of Formula (VI) are included in the pharmaceutical compositions of the invention and are used in the methods of the invention.

By the term "protected hydroxy" or "-OH protected ", as used in this document, the alcoholic or carboxylic OH groups that can be protected with conventional blocking groups in the art such as described in "Protective Groups In Organic Synthesis" by Theodora W. Greene, Wiley-Interscience, 1981, NY. Compounds containing hydroxy groups also they can be useful as intermediates in the preparation of Pharmaceutically active compounds of the invention.

By the term "aryl", as used in this document, a cyclic or polycyclic aromatic ring is understood containing 1 to 14 carbon atoms and containing optionally one to five heteroatoms, with the proviso that when the number of carbon atoms is 1 the aromatic ring contain at least four heteroatoms, when the number of atoms carbon be 2 the aromatic ring contains at least three heteroatoms, when the number of carbons is 3 the ring aromatic contain at least two heteroatoms and when the number of carbon atoms be 4 the aromatic ring contains at least one heteroatom.

By the term "aryl C_ {1} -C_ {12} ", as used in this document, it is understood phenyl, naphthalene, 3,4-Methylenedioxyphenyl, pyridine, biphenyl, quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole and tetrazole.

When referring to compounds of Reference Formula (I) and (II), the term "substituted", as  used in this document, refers to the chemical entity subject has one or more substituents selected from the group constituted by: -CO 2 R 20, aryl, -C (O) NHS (O) 2 R 20, -NHS (O) 2 R 20, hydroxyalkyl, alkoxy, -C (O) NR 21 R 22, acyloxy, alkyl, amino, N-acylamino, hydroxy, - (CH 2) g C (O) OR 8, -S (O) n R 8, nitro, tetrazol, cyano, oxo, halogen, trifluoromethyl, protected -OH and a methylene substituent heterocyclic as represented by Formula (III),

7

in which g is 0-6; R 8 is hydrogen or alkyl; R 20 is selected from hydrogen, C1-C4 alkyl, aryl and trifluoromethyl; R 21 and R 22 are selected independently between hydrogen, alkyl C 1 -C 4, aryl and trifluoromethyl; each of V, W, X and Z is independently selected from O, S and NR 16, where R 16 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, alkyl substituted, substituted cycloalkyl and aryl C_ {1} -C_ {12} substituted: and n is 0-2.

When referring to compounds of Formula (VI), the term "substituted", as used herein, refers to the subject chemical moiety having one or more substituents selected from the group consisting of: -CO_ {2} R 20, aryl, -C (O) NHS (O) 2 R 20, -NHS (O) 2 R 20, hydroxyalkyl, alkoxy, -C (O ) NR 21 R 22, acyloxy, alkyl, amino, N-acylamino, hydroxy, - (CH 2) g C (O) OR 8, -S (O) R 8, nitro, tetrazol, cyano, oxo, halogen, trifluoromethyl and -OH protected, where g is 0-6, R 8 is hydrogen or alkyl, R 20 is selected from hydrogen, C 1 -C 4 alkyl, aryl and trifluoromethyl, and R 21 and R 22 are independently selected from hydrogen, C 1 -C 4 alkyl, aryl and trifluoromethyl , and n is
0-2.

By the term "alkoxy", as used in This document means -Olkyl where alkyl It is as described in this document, including -OCH_ {3} and -OC (CH 3) 2 CH 3.

The term "cycloalkyl," as used in This document refers to a group C 3 -C 12 non-aromatic, saturated or unsaturated, cyclic or polycyclic.

Examples of cycloalkyl substituents and substituted cycloalkyl, as used herein, includes: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl-4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl, cyclopropyl and cyclopentyl

By the term "acyloxy", as used in This document means -OC (O) alkyl where the alkyl is as described herein. The examples of acyloxy substituents, as used herein, include: -OC (O) CH 3, -OC (O) CH (CH 3) 2 and -OC (O) (CH 2) 3 CH 3.

For the term "N-acylamino", as used herein, it is understood -N (H) C (O) alkyl, where the alkyl is as described in this document. The examples of N-acylamino substituents, as used herein document, include: -N (H) C (O) CH 3, -N (H) C (O) CH (CH 3) 2 Y -N (H) C (O) (CH 2) 3 CH 3.

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By the term "aryloxy," as used in This document means -Oarilo where the aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy, - (CH 2) g C (O) OR 8, -S (O) n R 8, nitro, cyano, halogen and  -OH protected, where g is 0-6, R 8 is hydrogen or alkyl, and n is 0-2. The examples of aryloxy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.

By the term "heteroatom", as used in this document, oxygen, nitrogen or sulfur is understood.

By the term "halogen", as used in This document means a substituent selected from bromide, iodide, chloride and fluoride.

By the term "alkyl" and derivatives of same and in all carbon chains, as used in this document, is a linear hydrocarbon chain or branched, saturated or unsaturated, and the carbon chain will contain from 1 to 12 carbon atoms. Examples of alkyl substituents, as used herein, include: -CH_ {3}, -CH_ {2} -CH_ {3}, -CH_ {2} -CH_ {2} -CH_ {3}, -CH (CH 3) 2, -C (CH 3) 3,  - (CH 2) 3 -CH 3, -CH 2 -CH (CH 3) 2, -CH (CH 3) - CH 2 -CH 3, -CH = CH 2, and-CDC-CH 3.

By the term "treat" and derivatives of same, as used in this document, therapy is understood Prophylactic and therapeutic.

The compounds of Formula (VI) are included in the pharmaceutical compositions of the invention and are used in the methods of the invention. When a group is present  -COOH or -OH, esters can be used pharmaceutically acceptable, for example methyl, ethyl, pivaloyloxymethyl and the like for -COOH, and acetate, maleate and the like for -OH, and known esters in the art to modify the solubility characteristics or hydrolysis, for use as prodrug formulations or sustained release

The new compounds of Reference Formulas I and II are prepared as shown in Schemes I to IV a then, or by analogous procedures, where the substituents 'R', AR, Y and m are as defined in Reference Formulas I and II, respectively, and on the condition that the substituents 'R' and m, AR and Y do not include any of these substituents that render the procedures of Schemes I to IV inoperative. Everybody starting materials are available in the market or are easily prepare from available starting materials in the market by specialists in the art.

Scheme I

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8

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i) Nitric acid; sulfuric acid; ii) 4-carboxyphenylboronic acid; Pd (PPh 3) 4. Na 2 CO 3 dioxane, water; iii) H2, Pd-C; iv) NaNO2, AR, NaHCO3, Water, EtOH

Scheme I summarizes the formation of compounds of Reference Formula I. As used in scheme I, a 3-bromophenol (a) is nitrated with nitric acid or sodium nitrate and sulfuric acid to give the nitro phenol (b). The coupling of (b) with a substituted arylboronic acid, such as 3-carboxyphenylboronic acid or 4-carboxyphenylboronic acid in the presence of a catalyst, preferably palladium tetrakis triphenylphosphine and a base such as sodium carbonate or triethylamine in a suitable solvent such as 1, Aqueous 4-dioxane or dimethylformamide produces the substituted aryl compound (c). Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as tin dichloride iron in a suitable solvent such as ethanol, acetic acid or water gives the aniline (d). The compound (d) is diazotized by reaction with sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as water or, preferably, an ethanol-water mixture. to produce a kind of diazonium that is converted directly into the compound (e) in a coupling reaction with an appropriate aryl species in the presence of a base, preferably sodium carbonate, or an acid, preferably hydrochloric acid.

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Scheme II

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9

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i) NaNO2, sulfuric acid; ii), MeI, K2CO3, acetone; iii) acid 3-carboxyphenylboronic; Pd (PPh 3) 4, Na 2 CO 3, dioxane, water; iv) HBr ac. 48%, AcOH; v) H2, Pd-C; saw) NaNO2, AR, NaHCO3, water, EtOH

Scheme II summarizes an alternative synthesis of compounds of Reference Formula I. A 2-bromophenol (f) (such as 2-bromophenol or 2-bromo-5-methylphenol) is nitrated with nitric acid or sodium nitrate and sulfuric acid, to give the nitro compound (g). The phenol (g) is then protected by reaction with an alkylating agent such as benzyl bromide or preferably methyl iodide in the presence of a base such as sodium hydride or potassium carbonate in a suitable solvent such as dimethylformamide, tetrahydrofuran or acetone for give the protected nitrophenol (h) (Prot = alkyl or substituted alkyl, for example methyl, benzyl). The coupling of (h) with a substituted arylboronic acid, such as 3-carboxyphenylboronic acid or 4-carboxyphenylboronic acid, in the presence of a catalyst, preferably tetrakyl triphenylphosphine palladium and a base such as sodium carbonate or triethylamine in a suitable solvent such as 1 , Aqueous 4-dioxane or dimethylformamide produces the substituted aryl compound (i). Removal of the protective group (Prot) is performed using a protic or Lewis acid; such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to produce the phenol (j). The reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as tin dichloride iron in a suitable solvent such as ethanol, acetic acid; or water gives the aniline (k). The compound (k) is diazotized by reaction with sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as water or, preferably, an ethanol-water mixture. to produce a kind of diazonium that is converted directly into the compound (1) in a coupling reaction with an appropriate aryl species in the presence of a base, preferably sodium carbonate, or an acid, preferably hydrochloric acid.

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Scheme III

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10

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i) 5- (3-bromophenyl) tetrazole, Pd (PPh3) 4, Na2CO3, dioxane, water; ii) HBr ac. 48%, AcOH; iii) HNO2, AcOH; iv) H2, Pd-C; v) NaNO2, AR, NaHCO3, water, EtOH

Scheme III summarizes an additional procedure for the synthesis of compounds of Reference Formula I. A protected hydroxyphenylboronic acid (m) (Prot = alkyl or substituted alkyl, for example methyl, benzyl) such as 5-chloro-2-methoxyphenylboronic acid, 5-Fluoro-2-methoxyphenyl, boronic acid or 2-methoxy-5-formylphenylboronic acid, is coupled with a species of substituted halogenoaryl, such as 5- (3-bromophenyl) tetrazole or 5-bromonicotinic acid, in the presence of a catalyst , preferably tetrakis triphenylphosphine palladium, and a base, such as sodium carbonate or triethylamine in a suitable solvent such as aqueous 1,4-dioxane or dimethylformamide, yielding the substituted aryl compound (n). Removal of the Prot protecting group is performed using a protic or Lewis acid, such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to produce the phenol (o). Nitration of (o) with nitric acid, or sodium nitrate in the presence of an acid, such as acetic acid or hydrochloric acid, produces the nitro compound (p). Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as tin dichloride iron in a suitable solvent such as ethanol, acetic acid or water gives the aniline (q). The compound (q) is diazotized by reaction with sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as water or, preferably, an ethanol-water mixture. to produce a kind of diazonium that is converted directly into the compound (r) in a coupling reaction with an appropriate aryl species in the presence of a base, preferably sodium carbonate, or an acid, preferably hydrochloric acid.

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Scheme IV

eleven

i) NaNO2, HCl, water and then SnCl2, water; ii) AcOH, hot.

Scheme IV summarizes the formation of pyrazoles for use in scheme I-III. An amine such as 4-methylaniline, the compound (s), is diazotized by the action of sodium nitrite and an appropriate acid, such as hydrochloric acid, nitric acid or sulfuric acid, in an appropriate aqueous solvent system, such as water or mixtures of ethanol-water, and then reduced in situ with tin chloride to produce hydrazine, compound (t). The hydrazine is then condensed with an electrophilic carbonyl species such as ethyl acetoacetate (u), ethyl cyanoacetate or diethyl malonate, in an appropriate solvent such as acetic acid or ethanol at an appropriate temperature, typically 0-100 ° C, to give the corresponding pyrazole, compound (v) as described herein.

A procedure is provided to prepare a compound of Formula (VI), the reaction process comprising of a compound of Formula (VII)

12

or a protected form thereof with a compound of Formula (VIII) or a tautomeric equivalent (IX)

13

where:

quad

R is a phenyl or pyridinyl ring substituted with one or more of the following:

-C (O) OH, tetrazole, sulfonic acid, hydroxy, methyl, fluoro, NHSO2 CF3 and C (O) NHSO 2 CH 3; and R1 is hydrogen,

or:

quad

R is hydrogen; and R1 is a phenyl ring or pyridinyl substituted with one or more of the following: -C (O) OH, tetrazole, sulfonic acid, hydroxy, methyl, fluoro, NHSO2 CF3, and C (O) NHSO 2 CH 3;

and in any case:

quad

R 2 and R 3 are independently selected between hydrogen, C 1-6 alkyl and halogen;

quad

R 15 is selected from the constituted group by: C 1-6 alkyl, alkoxy C 1-6, trifluoromethyl and halogen; and

quad

And you select between,

quad

phenyl that is optionally substituted with each other three substituents selected from the group consisting of: alkyl, substituted alkyl, trifluoromethyl and halogen; Y

followed, if necessary or desired, of salt formation

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In the preparation of the compounds of Formula of Reference (I) of the present invention, the following novel intermediates:

Acid 4'-amino-3'-hydroxybiphenyl-4-carboxylic acid;

Acid 4'-amino-3'-hydroxybiphenyl-3-carboxylic acid;

Acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3'-amino-2'-hydroxybiphenyl-4-carboxylic acid;

3-amino-2-hydroxy-3 '- (1 H -tetrazol-5-yl) biphenyl;

3-amino-2-hydroxy-4 '- (1 H -tetrazol-5-yl) biphenyl;

3-amino-5-chloro-2-hydroxy-4 '- (1 H -tetrazol-5-yl) -biphenyl;

Acid 6- (3-amino-2-hydroxyphenyl) pyridine-2-carboxylic acid;

Acid 6- (3-amino-5-chloro-2-hydroxyphenyl) pyridine-2-carboxylic acid;

Acid 6- (3-amino-2-hydroxy-5-methylphenyl) pyridine-2-carboxylic acid;

Acid 5- (3-amino-2-hydroxyphenyl) nicotinic;

Acid 5- (3-amino-2-hydroxy-5-methylphenyl) nicotinic;

Acid 2- (3-amino-2-hydroxyphenyl) isonicotinic;

Acid 3'-amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid;

Acid 3'-amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3'-amino-5'-chloro-2'-hydroxybiphenyl-3-carboxylic acid;

Acid 3'-amino-2'-hydroxybiphenyl-3,5-dicarboxylic;

N- [1- (3'-amino-2'-hydroxybiphenyl-3-yl) methanoyl] methanesulfonamide;

N- (3'-amino-2'-hydroxybiphenyl-3-yl) -1,1,1-trifluoro-methanesulfonamide;

Acid (3'-amino-2'-hydroxybiphenyl-3-yl) phosphonic;

Acid 3'-amino-2'-hydroxybiphenyl-3,4-dicarboxylic;

Acid 3'-amino-4,2'-dihydroxybiphenyl-3-carboxylic acid;

Acid 3'-amino-2'-hydroxybiphenyl-3-sulfonic;

Acid 3'-hydroxy-4'-nitrobiphenyl-4-carboxylic;

Acid 3'-hydroxy-4'-nitrobiphenyl-3-carboxylic acid;

Acid 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid;

Acid 2'-hydroxy-3'-nitrobiphenyl-4-carboxylic;

5-chloro-2-hydroxy-3-nitro-3 '- (1 H -tetrazol-5-yl) biphenyl;

5-chloro-2-hydroxy-3-nitro-4 '- (1 H -tetrazol-5-yl) biphenyl;

Acid 6- (5-Chloro-2-hydroxy-3-nitrophenyl) pyridine-2-carboxylic acid;

Acid 6- (2-hydroxy-5-methyl-3-nitrophenyl) pyridine-2-carboxylic acid;

Acid 5- (5-Chloro-2-hydroxy-3-nitrophenyl) nicotinic;

Acid 5- (5-Chloro-2-hydroxy-5-methyl-3-nitrophenyl) nicotinic;

Acid 2- (5-Chloro-2-hydroxy-3-nitrophenyl) isonicotinic;

Acid 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid;

Acid 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3,5-dicarboxylic acid;

N- [1- (5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-yl) methanoyl] methanesulfonamide;

1,1,1-Trifluoro-N- (2'-hydroxy-3'-nitrobiphenyl-3-yl) methanesulfonamide;

Acid (5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-yl) phosphonic;

Acid 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3,4-dicarboxylic acid;

Acid 5'-Chloro-4,2'-dihydroxy-3'-nitrobiphenyl-3-carboxylic acid;

Acid 5'-chloro-2'-hydroxy-3'-nitrobiphenyl-3-sulfonic;

Acid 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid;

Acid 2'-methoxy-3'-nitrobiphenyl-4-carboxylic;

5-chloro-2-hydroxy-3 '- (1 H -tetrazol-5-yl) biphenyl;

5-chloro-2-hydroxy-4 '- (1H-tetrazol-5-yl) biphenyl;

Acid 6- (5-Chloro-2-hydroxyphenyl) pyridine-2-carboxylic acid;

Acid 6- (2-hydroxy-5-methylphenyl) pyridine-2-carboxylic acid;

Acid 6- (2-hydroxy-5-methylphenyl) pyridine-2-carboxylic acid;

Acid 5- (5-Chloro-2-hydroxy-5-methylphenyl) nicotinic;

Acid 2- (5-Chloro-2-hydroxyphenyl) isonicotinic;

Acid 5'-Chloro-2'-hydroxybiphenyl-3-carboxylic acid;

Acid 5'-Chloro-2'-hydroxybiphenyl-3,5-dicarboxylic acid;

N- [1- (5'-Chloro-2'-hydroxybiphenyl-3-yl) methanoyl] methanesulfonamide;

3'-amino-3-nitrobiphenyl-2-ol;

Acid (5'-chloro-2'-hydroxybiphenyl-3-yl) phosphonic;

Acid 5'-Chloro-2'-hydroxybiphenyl-3,4-dicarboxylic acid;

Acid 5'-Chloro-4,2'-dihydroxybiphenyl-3-carboxylic acid;

Acid 5'-chloro-2'-hydroxybiphenyl-3-sulfonic;

5-chloro-2-methoxy-3 '- (1 H -tetrazol-5-yl) biphenyl;

5-chloro-2-methoxy-4 '- (1H-tetrazol-5-yl) biphenyl;

Acid 6- (5-Chloro-2-methoxyphenyl) pyridine-2-carboxylic acid;

Acid 6- (2-Methoxy-5-methylphenyl) pyridine-2-carboxylic acid;

Acid 6- (2-Methoxy-5-methylphenyl) pyridine-2-carboxylic acid;

Acid 5- (5-Chloro-2-methoxy-5-methylphenyl) nicotinic;

Acid 2- (5-Chloro-2-methoxyphenyl) isonicotinic;

Acid 5'-Chloro-2'-methoxybiphenyl-3-carboxylic acid;

Acid 5'-Chloro-2'-methoxybiphenyl-3,5-dicarboxylic acid;

N- [1- (5'-Chloro-2'-methoxybiphenyl-3-yl) methanoyl] methanesulfonamide;

N- (2'-methoxy-3'-nitrobiphenyl-3-yl) -acetamide;

Acid (5'-Chloro-2'-methoxybiphenyl-3-yl) phosphonic;

Acid 5'-Chloro-2'-methoxybiphenyl-3,4-dicarboxylic acid;

Acid 5'-Chloro-4-hydroxy-2'-methoxybiphenyl-3-carboxylic acid; Y

Acid 5'-Chloro-2'-methoxybiphenyl-3-sulfonic.

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The treatment of thrombocytopenia, as described in this document, is done by increasing the production of platelets

For the term "co-administration" and derivatives thereof, such as it is used in this document, it is intended to indicate the administration simultaneous or any form of sequential administration by separated from a mimetic TPO compound, as described in this document, and an additional active ingredient or ingredients, known to treat thrombocytopenia, including Chemotherapy-induced thrombocytopenia and bone marrow transplantation bone and other conditions with decreased platelet production. He term ingredient or additional active ingredients, as used herein, includes any compound or agent therapeutic known for or demonstrating advantageous properties when administered with TPO or a TPO mimetic. Preferably, if administration is not simultaneous, the compounds are administered in close temporal proximity to each other. Also, it doesn't matter if the compounds are administered in the same dosage form, by example a compound can be administered topically and another Compound can be administered orally.

Examples of an ingredient or ingredients additional assets for use together with the mimetic compounds of TPOs of the present invention include, but are not limited to:

agents chemoprotectors or myeloprotectors such as G-CSF, BB 10010 (Clemons et al., Breast Cancer Res. Treatment, 1999, 57, 127), amifostine (Ethyol) (Fetscher et al., Current Opinion in Hemat., 2000, 7, 255-60), SCF, IL-11, MCP-4, IL-1-beta, AcSDKP (Gaudron et al., Stem Cells, 1999, 17, 100-6), TNF-a, TGF-b, MIP-1a (Egger et al., Bone Marrow Transpl., 1998, 22 (Suppl. 2), 34-35) and others molecules identified as having properties anti-apoptotic, survival or proliferative

TPO has been shown to act as a peripheral blood stem cell mobilizer (Neumann T. A. et al., Cytokines, Cell. & Mol. Ther., 2000, 6, 47-56). This activity can synergize with stem cell mobilizers such as G-CSF (Somolo et al., Blood, 1999, 93, 2798-2806). For the therefore, the TPO mimetic compounds of the present invention are useful in increasing the number of stem cells in circulation in donors before leukophoresis for Hematopoietic stem cell transplantation in patients who receive myeloablative chemotherapy.

Similarly, TPO stimulates the growth of myeloid cells, particularly those of the lineage of granulocytes / macrophages (Holly et al., document US-5989537). The parents of granulocytes / macrophages are cells of the myeloid lineage that mature as neutrophils, monocytes, basophils and eosinophils. Thus, the compounds described in the present invention have utility therapeutic in the stimulation of neutrophil proliferation in  patients with neutropenic conditions.

Other examples of an ingredient or ingredients additional assets for use together with the mimetic compounds of TPO of the present invention include, but are not limited to: cells mother, megakaryocyte, neutrophil mobilizers such as agents chemotherapeutics (i.e. cytoxane, etoposide, cisplatin, Ballestrero A. et al., Oncology, 2000, 59, 7-13), chemokines, IL-8, Gro-beta (King, A. G. et al. J. Immun., 2000, 164, 3774-82), agonist antibodies or receptor antagonists, cytokines of small molecules or receptor agonists or antagonists, SCF, Lingt Flt3, molecule and adhesion inhibitors or antibodies such as: anti-VLA-4 (Kikuta T. and col., Exp. Hemat., 2000, 28, 311-7) or anti-CD44 (Vermeulen M. et al., Blood, 1998, 92, 894-900), cytokine / chemokine / interleukin or agonist or receptor antagonist antibodies, MCP-4 (Berkhout TA., Et al., J. Biol. Chem., 1997, 272, 16404-16413; Uguccioni M. et al., J. Exp. Med., 1996, 183, 2379-2384).

As the pharmacologically active compounds of the present invention are active as TPO mimetics, show therapeutic utility in the treatment of thrombocytopenia and other conditions with decreased platelet production.

For the term "thrombocytopenia" and derivatives thereof, as used herein, must interpret any reduction in the number of blood platelets below normal or desired For a healthy individual. It is known that thrombocytopenia has many causative factors, including but not limited to therapy radiation, chemotherapy, immunotherapy, thrombocytopenic purpura Immune (ITP, Bussel J. B., Seminars in Hematology, 2000, 37, Suppl 1,1-49), myelodysplastic syndrome (MDS), anemia aplastic, AML, CML, viral infections (including, but not limitation; HIV, hepatitis C, parvovirus), liver disease, myeloablation, bone marrow transplant, cell transplant mother, peripheral blood cell transplant, defect of progenitor cells, polymorphisms in stem cells and cells parents, TPO defects, neutropenia (Sawai, N. J. Leukocyte Biol., 2000, 68, 137-43), cell mobilization dendritic (Kuter D. J. Seminars in Hematology. 2000, 37, Suppl 4, 41-49), proliferation, activation or differentiation. The pharmaceutically active compounds of this invention are useful in the treatment of thrombocytopenia regardless of factor or factors that cause the condition. The compounds Pharmaceutically active of this invention are also useful in thrombocytopenia treatment when the factor or factors that cause the condition are unknown or should still be identified.

The prophylactic use of the compounds of this invention is contemplated when a decrease in blood or platelets in blood. The prophylactic use of compounds of this invention results in an accumulation of platelets or a start of platelet production before a anticipated loss of blood or platelets in the blood. The uses Prophylactic compounds of this invention include, but are not limitation, transplant surgery, surgery, anesthesia prior to Birth of children and intestinal protection.

It has been shown that dendritic cells humans express the TPO receptor (Kumamoto et al., Br. J. Haem, 1999, 105, 1025-1033) and TPO is a powerful dendritic cell mobilizer. TPO mimetic compounds of the present invention are also useful as an adjuvant of vaccine in which the activity and mobility of dendritic cells The pharmaceutically active compounds of This invention are useful as an immune adjuvant, provided together with a vaccine and / or immunomodulator administered orally, transdermally or subcutaneously, increasing activity and dendritic cell mobility.

It is known that TPO has several effects, including anti-apoptotic / survival effects on megakaryocytes, platelets and stem cells, and proliferative effects on stem cells and megakaryocyte cells (Kuter D. J. Seminars in Hematology, 2000, 37, 41-9). These TPO activities effectively increase the number of cells mother and parents so that there is a synergistic effect when Tpo is used together with other cytokines that induce differentiation.

The TPO mimetic compounds of the present invention are also useful acting in cells for the survival or proliferation along with other agents known that act on cells for survival or proliferation. These other agents include, but are not limited to: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11, SCF, ligand FLT3, LIF, IL-3, IL-6, IL-1, Progenipoietin, NESP, SD-01 or IL-5 or a biologically active derivative of any of the agents mentioned above, KT6352 (Shiotsu Y. et al., Exp. Hemat. 1998, 26, 1195-1201), uteroferrin (Laurenz JC., And cabbage. Comp. Biochem & Phys., Part A. Physiology., 1997, 116, 369-77), FK23 (Hasegawa T., et al. Int. J. Immunopharm., 1996, 18 103-112) and other molecules identified as property owners anti-apoptotic, survival or proliferative for stem cells, progenitor cells or other cells that express Tpo receptors.

When determining the power as TPO mimetics, the following tests were used:

Luciferase Assay

The compounds of the present invention are tested to determine their potency as receptor mimetics of TPO in a Luciferase assay as described in Lamb, and col., Nucleic Acids Research 23: 3283-3289 (1995) and Seidel, et al., Proc. Natl Acad. Sci., USA 92: 3041-3045 (1995) using a BaF3 cell line TPO sensitive (Vigon et al. Proc. Natl. Acad. Sci. USA 1992, 89, 5640-5644) instead of the HepG2 cells used in that document. Murine BaF3 cells express receptors from TPO and closely match the STAT activation pattern (signal transducers and transcription activators) observed in primary murine and human bone marrow cells.

Proliferation Assay

Some of the most preferred compounds of this invention were active in an in vitro proliferation assay using the human UT7TPO cell line. UT7TPO cells are a human magacarioblastic cell line that expresses TPO-R, whose survival and growth depends on the presence of TPO (Komatsu et al. Blood 1996, 87,4552).

Differentiation Test

Similarly, some of the compounds more preferred of this invention were also positive in the stimulation of megakaryocyte maturation from cells of human bone marrow. In this assay, cells were incubated purified human CD34 + progenitors in liquid culture with test compounds for 10 days and then the number was measured of cells expressing CD41 transmembrane glycoprotein (gpIIb), a megakaryocyte marker, by flow cytometry (see Cwirla, S. E. et al. Science, 1997, 276, 1696).

The pharmaceutically active compounds within of the scope of this invention are useful as TPO mimetics in mammals, particularly in humans, who need them.

Some of the preferred compounds within the scope of the invention showed activation of approximately the 4% to 100% control at a concentration of 0.001-10 µM in the luciferase assay. The Preferred compounds of the invention also enhanced the proliferation of UT7TPO and 32D-mpl cells at a concentration of 0.003 to 30 µM. Preferred compounds of the invention also showed activity in the megakaryocyte assay of CD41 at a concentration of 0.003 to 30 µM.

The drug can be administered to a patient who you need it by any convenient administration route, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal and parenteral.

The pharmaceutically active compounds of the Present invention are incorporated into dosage forms suitable such as capsules, tablets or preparations injectable Solid or liquid pharmaceutical vehicles are used. Solid vehicles include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar gum, pectin, gum arabic, magnesium stearate and stearic acid. The Liquid vehicles include syrup, peanut oil, oil Olive, saline and water. Similarly, the vehicle or Diluent can include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid vehicle varies broadly but, preferably, will be about 25 mg at approximately 1 g per dosage unit. When a liquid vehicle, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, injectable liquid sterile such as a blister, or an aqueous liquid suspension or not watery

Pharmaceutical preparations are manufactured following conventional techniques of a pharmaceutical chemistry that involves mixing, granulation and compression, when necessary, for tablet forms, or mixing, loading and dissolution of ingredients, when appropriate, to give oral products or desired parenterals.

The doses of the compounds pharmaceutically assets of the present invention in a dosage unit pharmaceutical as described above will be an amount effective, non-toxic, preferably selected from the range of 0.001-100 mg / kg of active compound, preferably 0.001-50 mg / kg. When treating a patient human in need of a TPO mimetic, the selected dose is preferably administered 1-6 times a day, for oral or parenteral route. The forms of parenteral administration Preferred include topical, rectal, transdermal, injection and continue by infusion. The oral dosage units for administration to humans preferably contain from 0.05 to 3500 mg of active compound. Oral administration is preferred, who uses lower doses. However, it can also be used parenteral administration, at high doses, when it is safe and convenient for the patient.

The optimal doses to be administered will be determined easily by those skilled in the art, and will vary with the mimetic of particular TPO in use, the concentration of preparation, the route of administration and the progress of the pathology. Other factors that depend on the particular patient in question will result in the need to adjust the doses, including the age, weight and diet of the patient, and the time of administration.

The process of this invention to include mimetic activity of TPO in mammals, including humans, comprises administering to a subject that needs said activity a mimetic amount of effective TPO of a pharmaceutical compound active of the present invention.

The invention also provides the use of a compound of Formula (VI) in the preparation of a medicament for Use as a TPO mimetic.

The invention also provides the use of a compound of Formula (VI) in the preparation of a medicament for Use in therapy.

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The invention also provides the use of a compound of Formula (VI) in the preparation of a medicament for use in the enhancement of platelet production.

The invention also provides the use of a compound of Formula (VI) in the preparation of a medicament for use in the treatment of thrombocytopenia.

The invention also provides a composition. pharmaceutical for use as a TPO mimetic comprising a compound of Formula (VI) and a pharmaceutically carrier acceptable.

The invention also provides a composition. pharmaceutical for use in the treatment of thrombocytopenia that comprises a compound of Formula (VI) and a vehicle pharmaceutically acceptable.

The invention also provides a composition. pharmaceutical for use in promoting the production of platelets comprising a compound of Formula (VI) and a vehicle pharmaceutically acceptable.

No toxicological effect is expected. unacceptable when administering compounds of the invention of according to the present invention.

In addition, pharmaceutically active compounds of the present invention can be co-administered with other active ingredients, such as other known compounds to treat thrombocytopenia, including induced thrombocytopenia for chemotherapy and bone marrow transplantation and other conditions with decreased platelet production, or compounds known to be They are useful when used together with a TPO mimetic.

Contemplated Equivalents -  It will be appreciated by the person skilled in the art that the compounds of Reference Formulas I and II also They can exist in tautomeric forms. For example, in Formula I,  the double bond that is represented between the two nitrogen atoms It exists between the lower nitrogen atom and the AR substituent. Tautomeric forms of the compounds of the Formulas of Reference I and II are exemplified by the following Formula (IV):

14

in which the "R" groups are as defined above. All these compounds are included in the scope of the invention and included inherent in the definition of the compounds of the Formulas of Reference I and II.

Without further elaboration, it is believed that a Technician can use, using the description above, the present invention to its fullest extent.

Experimental Details

Example one

Acid preparation 4 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-4-carboxylic acid to) 5-Bromo-2-Nitrophenol

Slowly added 3-Bromophenol (32.9 g, 0.19 mol) in a cold solution (10 ° C) sodium nitrate (29.0 g, 0.34 mol) in sulfuric acid conc. (40.0 g) and water (70.0 ml) and the resulting mixture was left in stirring at room temperature for 2 h. Water was added (200 ml), the resulting mixture was extracted with diethyl ether and the extract was dried (MgSO 4), filtered and concentrated. The residue It was purified by flash chromatography (silica gel, acetate 10% ethyl / hexanes) to first produce the compound of title (8.1 g, 20%), m.p. 40-42 ° C after unwanted isomer, 3-bromo-4-nitrophenol, in the form of a yellow solid (12.7 g, 31%). m.p. 125-127 ° C.

b) Acid 3'-hydroxy-4'-nitrobiphenyl-4-carboxylic

A solution of the compound of Example 1a) (2.18 g, 0.01 mol), 4-carboxyphenylboronic acid (1.74 g, 0.0105 mol), aq sodium carbonate. 2M (10.0 ml; 0.02 mol) and tetrakis triphenylphosphine palladium (0) (0.5 g) in 1,4-dioxane (60.0 ml), stirred and refluxed under an atmosphere of nitrogen for 24 h.

The reaction mixture was cooled and evaporated and The residue was treated with aq. hydrochloric acid. 6 M (100 ml). He gray precipitate was filtered and washed well with water and then with diethyl ether to produce the title compound (2.3 g; 88%) in the form of a colorless solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.5-10.5 (s a, 2H), 8.06 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.6, 1.8 Hz, 1H).

c) Acid 4'-amino-3'-hydroxybiphenyl-4-carboxylic acid, hydrochloride salt

A solution of the compound of Example 1b) (1.6 g, 0.0062 mol) in ethanol (75.0 ml), water (50.0 ml) and hydroxide sodium ac. 3M (2.0 ml, 0.0062 mol) was hydrogenated on palladium at 10% on carbon (0.2 g) at room temperature and at 344.74 kPa (50 psi) for 2 h.

The reaction mixture was filtered, treated with ac hydrochloric acid 3 M (25.0 ml), then evaporated and the residue was triturated with a small amount of water to produce the title compound (1.18 g; 72%) in the form of a colored solid brown. 1 H NMR (300 MHz, d 6 -DMSO) δ 10.90 (s, 1H), 10.5-8.5 (s a, 3H), 8.03 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.22 (dd, J = 8.2, 1.6 Hz, 1H).

d) 1- (3,4-Dimethylphenyl) -3-methyl-3-pyrazolin-5-one

A hydrochloride solution of 3,4-dimethylphenylhydrazine (17.7 g; 0.1 mol), ethyl acetoacetate (13.0 g; 0.1 mol) and sodium acetate (8.2 g; 0.1 mol) in glacial acetic acid (250 ml), stirred and heated to reflux for 24 h. The mixture was cooled and evaporated and the residue it was dissolved in diethyl ether (1 L) and washed carefully with sodium carbonate ac. sat. (5 x 200 ml). The etheric layer is evaporated to produce the title compound (15.4 g; 76%). 1 H NMR (300 MHz, d 6 -DMSO) δ 11.30 (s a, 1H), 7.49 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.2 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 5.31 (s, 1H), 2.20 (s, 3H), 2.22 (s, 3H), 2.08 (s, 3 H); MS (ES) m / z 203 [M + H].

e) Acid 4 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-4-carboxylic acid;  hemihydrate

A suspension of the compound of Example 1c) (1.0 g; 0.0044 mol) in aq. Hydrochloric acid. 1 M (15.0 ml) cooled to 5 ° C and then treated dropwise with a solution of sodium nitrite (0.32 g; 0.0046 mol) in water (5.0 ml). The mixture of yellow color was stirred at 5 ° C for a further 10 min and then treated in one portion with the compound of Example 1d) (0.882 g, 0.0044 mol) followed by portion addition of sodium acid carbonate (1.8 g; 0.022 mol) and ethanol (20.0 ml) ensuring that the final pH of The reaction mixture was about 7-8. Then, the red solution was stirred at room temperature for 24 h.

The mixture was filtered to give a colored solid. red which was suspended in water (50.0 ml) and then acidified with concentrated hydrochloric acid. Filtration produced the compound. of the title (0.68 g; 35%) in the form of an orange powder, m.p. = 280 ° C (dec.). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.62 (s, 1H), 13.2-12.2 (s a, 1H), 10.92 (s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.73-7.69 (m, 5H), 7.63 (d, 8.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.2 (s, 3H); Anal. (C 25 H 22 N 4 O 4 {0.5 H 2 O) calc .: C, 66.51; H, 5.13; N, 12.41, found: C, 66.74; H, 5.08; N, 12.36.

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Example 2 Acid preparation 4 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-3-carboxylic acid a) Acid 3'-hydroxy-4'-nitrobiphenyl-3-carboxylic

Following the procedure of Example 1b), with the exception that acid was used 4-carboxyphenylboronic acid instead 3-carboxyphenylboronic, the compound of the title (1.75 g; 68%) in the form of a brown powder. 1 H NMR (300 MHz, d 6 -DMSO) δ 13.16 (s a, 1H), 11.18 (s, 1H), 8.20 (d, J = 0.9 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.96 (dd, J = 7.8, 0.9 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H).

b) Acid 4-amino-3'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt

Following the procedure of Example 1c), with the exception that acid was used 3'-hydroxy-4'-nitrobiphenyl-3-carboxylic  instead of acid 3'-hydroxy-4'-nitrobiphenyl-4-carboxylic acid, the title compound (1.32 g; 83%) was prepared as a solid brown. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 10.96 (s, 1H), 10.5-9.5 (s a, 3H), 8.12 (t, J = 2.6 Hz, 1H), 7.96 (dt, J = 7.9, 1.3 Hz, 1H), 7.86 (dt, J = 8.2, 1.3 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.2, 1.9 Hz, 1H).

c) Acid 4 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of Example 1e), with the exception that acid was used 4-amino-3'-hydroxybiphenyl-3-carboxylic acid,  hydrochloride salt instead of acid 4-amino-3'-hydroxybiphenyl-4-carboxylic acid, hydrochloride salt, the title compound was prepared (1.04 g; 62%) in the form of an orange solid. m.p. 282 ° C (dec.). 1 H NMR (300 MHz, d6 -DMSO) δ 13.66 (s, 1H), 13.15 (s, 1H), 10.89 (s, 1H), 8.16 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.73-7.71 (m, 2H), 7.65-7.57 (m, 2H), 7.32-7.30 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H); Anal. (C 25 H 22 N 4 O 4 {0.25 H 2 O) calc .: C, 67.18; H, 4.97; N, 12.53, found: C, 67.26; H, 4.96; N, 12.46.

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Example 3 Acid preparation 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2-Bromo-6-Nitrophenol

Following the procedure of Example 1a) with the exception that 2-bromophenol was used instead of 3-Bromophenol, the title compound was prepared (10.9 g; 25%) in the form of a bright yellow solid. 1 H NMR (300 MHz, CDCl 3) δ 11.10 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 6.90 (t, J = 7.9 Hz, 1 HOUR).

b) 2-Bromo-6-nitroanisole

A mixture of the compound of Example 2a) (10.8 g; 0.0495 mol), methyl iodide (3.4 ml; 0.00545 mol) and carbonate Potassium (8.2 g; 0.0592 mol) in acetone (250 ml), stirred and heated to reflux for 24 h.

The mixture was evaporated and the residue was triturated with water to produce the title compound (8.7 g; 76%). m.p. 55-56 ° C. 1 H NMR (300 MHz, CDCl 3) δ 7.81-7.74 (m, 2H), 7.13 (t, J = 8.1 Hz, 1H), 4.02 (s, 3H); Anal. (C 7 H 6 NO 3 Br) calc .: C, 36.24; H, 2.61; N, 6.04, found: C, 36.30; H, 2.59; N, 5.73.

c) Acid 2'-methoxy-3'-nitrobiphenyl-3-carboxylic

Following the procedure of Example 1b), with the exception that the compound of Example 3b) was used during 5-bromo-2-nitrophenol, and 3-carboxyphenylboronic acid was used instead of 4-carboxy boronic acid compound was prepared of the title (2.13 g; 47%) in the form of a brown powder. 1 H NMR (300 MHz, d6 -DMSO) δ 8.12 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.94 (dd, J = 7.9 Hz, 1.5 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.76 (dd, J = 7.5, 1.5 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 3.46 (s, 3H).

d) Acid 2'-hydroxy-3'nitrobiphenyl-3-carboxylic

A solution of the compound of Example 3c) (2.13 g; 0.0077 mol) in glacial acetic acid (25.0 ml) and acid hydrobromic ac. 48% (25.0 ml), stirred and heated to reflux for 5 h.

The mixture was cooled and filtered to produce the title compound (1.57 g; 79%) in the form of a brown powder. 1 H NMR (300 MHz, d 6 -DMSO) δ 13.90 (s, 1H), 10.66 (s, 1H), 8.12 (t, J = 1.7 Hz, 1H), 8.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.98 (dt, 7.8, 1.5 Hz, 1H), 7.79 (dt, J = 8.1, 1.7 Hz, 1H), 7.74 (dd, J = 7.5, 1.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.17 (dd, J = 8.4, 7.5 Hz, 1H).

e) Acid 3-amino-2'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt

Following the procedure of Example 1c), with the exception that the compound of Example 3d) was used instead of acid 3'-hydroxy-4'-nitrobiphenyl-4-carboxylic acid, the title compound (1.51 g; 100%) was prepared as a solid brown. 11.3-8.7 (s a, 4H), 8.08 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.8, 1.4 Hz, 1H), 7.24 (dd, J = 7.8, 1.3 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H).

f) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid,  hydrate

Following the procedure of Example 1e), with the exception that the compound of Example 3e) was used instead of acid 4'-amino-3'-hydroxybiphenyl-4-carboxylic acid, hydrochloride salt, the title compound was prepared (0.055 g; 32%) in the form of an orange solid. m.p. 228 ° C (dec.). 1 H NMR (300 MHz, d 6 -DMSO) δ 13.76 (s, 1H), 13.12 (s, 1H), 9.70 (s, 1H), 8.14 (s, 1H), 7.97 (dd, J = 7.7 Hz, 1H), 7.81 (dd, J = 7.7 Hz, 1H), 7.74-7.60 (m, 5H), 7.22-7.13 (m, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H); Anal. (C 25 H 22 N 4 O 4 {1.0 H 2 O) calc .: C, 65.21; H, 5.25; N, 12.17, found: C, 65.60; H, 4.96; N, 12.04.

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Example 4 Preparation of 3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid hemihydrate a) 1- (4- tert- Butyl) -3-methyl-3-pyrazolin-5-one

Following the procedure of example 1d), with the exception that 4- tert- butylphenylhydrazine hydrochloride was used instead of 3,4-dimethylphenylhydrazine hydrochloride, the title compound (13.8 g; 60%) was prepared. 1 H NMR (300 MHz, d 6 -DMSO) δ 11.32 (s, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 5.32 (s, 1H), 2.09 (s, 3H), 1.33 (s, 9H).

b) 3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxyphenyl-3-carboxylic acid hemihydrate

Following the procedure of Example 1e), with the exception that the compound of Example 3e) was used instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt and the compound of Example 4a) instead of 1- (3,4-dimethylphenyl) -3-methyl-3-pyrazolin-5-one, the title compound (0.391 g; 42%) was prepared as a solid orange, m.p. 145 ° C (dec.). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.76 (s, 1H), 13.07 (s, 1H), 9.72 (s, 1H), 8.14 (s, 1H), 7.98 (dd, J = 7.8, 1.2 Hz, 1H), 7.83 (t, J = 8.7 Hz, 1H), 7.73 (dd, J = 6.4, 3.1 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.20-7.16 (m, 2H), 2.35 (s, 3H), 1.31 (s, 9H). Anal. (C 27 H 26 N 4 O 4 {0.5 H 2 O) calc .: C, 67.63; H, 5.67; N, 11.68, found: C, 67.53; H, 5.46; N, 11.66.

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Example 5 2-aza-3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino acid -5'-chloro-2 acid '-hydroxybiphenyl-3-carboxylic

Following the procedure of Example 8, with the except that the compound of Example 4a was used instead of compound of Example 1d, the title compound was prepared in form of a red powder (0.08 g, 44%). MS (ES) m / z 506 [M + H].

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Example 6 2-Aza-3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 acid -carboxylic a) Acid 6- (5-Chloro-2-methoxyphenyl) -pyridine-2-carboxylic acid

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used acid 6-bromopyridine-2-carboxylic instead of the compound of 1a), the title compound was prepared (6.7 g; 100%) in the form of a white powder. MS (ES) m / z 264 [M + H].

b) Acid 6- (5-Chloro-2-hydroxyphenyl) -pyridine-2-carboxylic

Following the procedure of Example 3d), with the exception that the compound of 6a) was used instead of 3c compounds), the title compound was prepared (3.5 g; 74%) in the form of a gray powder. MS (ES) m / z 250 [M + H].

c) Acid 6- (5-Chloro-2-hydroxy-3-nitrophenyl) -pyridine-2-carboxylic acid

Following the procedure of Example 7c), with the exception that the compound of example 6b) was used instead of compound of example 7b), the title compound was prepared (1.3 g; 73%) in the form of a powder. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.71 (d, J = 9 Hz, 1H), 8.6 (d, J = 3.4 Hz, 1H), 8.33 (t, J = 8.6 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 3.4 Hz, 1H).

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d) 3-aza-3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl acid -3-carboxylic

Following the procedure of Example 1c), with the exception that the compound of 6c) was used instead of the compound 1b), the crude product was isolated. A product suspension crude (0.0033 mol) in aq. hydrochloric acid. 1 M (25.0 ml) cooled to 5 ° C and then treated dropwise with a solution of sodium nitrite (0.22 g; 0.0033 mol) in water (5.0 ml). The mixture of yellow color was stirred at 5 ° C for a further 10 min and then treated in one portion with the compound of Example 4a) (0.68 g, 0.003 mol) followed by portion addition of sodium carbonate and ethanol ensuring that the final pH of the reaction mixture was approximately 7-8. Then the color solution Red was stirred at room temperature for 24 h.

The mixture was filtered to give a colored solid. red which was suspended in water (50.0 ml) and then acidified with concentrated hydrochloric acid. Filtration produced the compound. of the title (0.95 g; 67%) in the form of a powder. MS (ES) m / z 472 (M + H) +.

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Example 7 3-aza-3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino acid -2 -2-hydroxybiphenyl-5 acid -carboxylic a) Acid 5- (5-Chloro-2-methoxyphenyl) -nicotinic

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 5-bromonicotinic acid instead of the compound of 1a), the title compound was prepared. MS (ES) m / z 264 [M + H].

b) Acid 6- (5-Chloro-2-hydroxyphenyl) -pyridine-2-carboxylic

Following the procedure of Example 3d), with the exception that compound 7a) was used instead of 3c compounds), the title compound was prepared. MS (ES) m / z 250 [M + H].

c) Acid 6- (5-Chloro-2-hydroxy-3-nitrophenyl) -pyridine-2-carboxylic acid

To the acid solution 6- (5-Chloro-2-hydroxyphenyl) -pyridine-2-carboxylic (2.3 g, 10.1 mmol) in 100 ml of acetic acid; 1 ml of smoking nitric acid; and stirred from 35 ° C to 40 ° C for half an hour. The reaction mixture was diluted with water and the pH adjusted to 2.5, The resulting precipitation was collected, washed and dried to give a solid (2.74 g; 78%, three stages). MS (ES) m / z 295 [M + H].

d) 2-Aza-3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl acid -3-carboxylic

Following the procedure of Example 1c), with the exception that the compound of 7c) was used instead of the compound 1b), the crude product was isolated. A product suspension in crude (0.0015 mol) in hydrochloric acid ac. 1 M (25.0 ml) cooled to 5 ° C and then treated dropwise with a solution of sodium nitrite (0.11 g; 0.0015 mol) in water (5.0 ml). The mixture of yellow color was stirred at 5 ° C for a further 10 min and then treated in one portion with the compound of Example 4a) (0.34 g, 0.0015 mol) followed by portion addition of sodium carbonate and ethanol ensuring that the final pH of the reaction mixture was approximately 7-8. Then the color solution Red was stirred at room temperature for 24 h. The mixture is filtered to give a red solid that was suspended in water (50.0 ml) and then acidified with concentrated hydrochloric acid. Filtration produced the title compound (0.2 g; 29%) as of a dust 1 H NMR (300 MHz, d 6 -DMSO) δ 13.8 (a, 2H), 9.9 (s, 1H), 9.08 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 7.82 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.20 (m, 2H), 2.34 (s, 3H), 1.32 (s, 9H) MS (ES) m / z 472 (M + H) +.

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Example 8 Acid 2-aza-5'-chloro-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2 ' -hydroxybiphenyl-3-carboxylic

The compound of Example 6c) (1 g, 3.39 mmol) in ethanol was treated with tin chloride (3.2 g, 17 mmol) and heated at reflux for 3 hours. After inactivating with 3 N hydrochloride, The precipitate was collected and washed with ether. 1.1 g of the raw product. Following the procedure of Example 1e), with the exception that the previous raw product was used instead of compound of Example 1c), the title compound was prepared in powder form (75%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.42 (d, J = 9.2 Hz, 1H), 8.2 (t, J = 8.0 Hz, 1H), 8.0 (m, 1H), 7.8 (s, 1H), 7.62 (m, 2H), 7.2 (d, J = 9.2 Hz, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H).

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Example 9 2-aza-3 '- {N' [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 'acid -methylbiphenyl-3-carboxylic acid a) Acid 6- (2-Hydroxy-5-methylphenyl) -pyridine-2-carboxylic acid

Following the procedure of Example 6a) and 6b), with the exception that acid was used 5-methyl-2-methoxy boronic instead of 2-methoxy boronic acid, it prepared the title compound as a solid (0.26 g, 31%, two stages). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.42 (d, J = 8.5 Hz, 1H), 8.2 (t, J = 8.2 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.9 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 2.22 (s, 3H).

b) Acid 6- (2-Hydroxy-3-amino-5-methylphenyl) -pyridine-2-carboxylic acid

Following the procedure of Example 7c), with the exception that the compound of example 9a) was used instead of compound of example 7b), crude product was isolated, dissolved again in ethanol and water and treated with 10% Pd / C. The mixture of reaction was stirred at 344.74 kPa (50 psi) of hydrogen for 3 hours before filtering and concentrating to give a green powder (80%) MS (ES) m / z 245 (M + H) +.

c) 2-Aza-3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy acid -5'-methylbiphenyl-3-carboxylic

Following the procedure of Example 4b), with the exception that the compound of example 9b) was used instead of compound of example 3e), the title compound was prepared in solid form (26%), 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.25 (d, J = 7.7 Hz, 1H), 8.15 (t, J = 7.7 Hz, 1H), 7.9 (m, 3H), 7.78 (s, 1H), 7.58 (s, 1H), 7.5 (d, J = 7.7 Hz, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 1.23 (s, 9H).

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Example 10 Acid 2-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 ' -methylbiphenyl-3-carboxylic acid

Following the procedure of Example 9), with the exception that 1- (3,4-dimethylphenyl) -3-methyl-3-pyrazolin-5-one was used instead of 1- (4- tert- butyl) -3 -methyl-3-pyrazolin-5-one, the title compound was prepared as a solid (40%). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.45 (d, J = 8.0 Hz, 1H), 8.25 (t, J = 8.0 Hz, 1H) , 8.05 (d, J = 8.0, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H ), 2.25 (s, 3H).

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Example 11 3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5'-methylbiphenyl- acid 3-carboxylic a) Acid 2'-hydroxy-5'-methylbiphenyl-3-carboxylic

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-methylphenylboronic  instead of 4-carboxyphenylboronic acid; and acid 3-Bromophenylcarboxylic instead of the compound of example 1a), the crude compound was isolated and treated with 1: 1 of hydrobromide and acetic acid. The reaction mixture was heated to reflux for 4 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The exact one was dried (MgSO4), filtered and concentrated, giving the title product (50%, two stages). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.23 (s, 1H), 8.1 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.1 (s, J = 8.2 Hz, 1H), 7.05 (s, 1H), 6.85 (d, J = 7.8 Hz, 1H), 2.15 (s, 3H).

b) Acid 2'-hydroxy-3-nitro-5'-methylbiphenyl-3-carboxylic

Following the procedure of example 7c), with the exception that example compound 11a) was used instead of example compound 7b), the title compound was prepared in form of a solid (0.4 g, 77%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.13 (s, 1H), 8.0 (d, J = 6.9 Hz, 1H), 7.84 (s, 1H), 7.8 (d, J = 6.9 Hz, 1H), 7.6 (m, 2H), 2.3 (s, 3H).

c) 3 '- {N' - [1- (4- tert -butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5'- methylbiphenyl-3-carboxylic acid

Following the procedure of example 7d), with the exception that example compound 11b) was used instead of example compound 7c), the title compound was prepared in form of a solid (0.003 g, <10%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.13 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.7 Hz, 2H), 7.72 (m, 2H), 7.61 (t, J = 7.7 Hz, 2H), 7.53 (s, 1H), 7.5 (d, 8.0 Hz, 2H), 2.33 (s, 6H), 1.22 (s, 9H). MS (ES) m / z 485 (M + H) +.

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Example 12 3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3' - (tetrazol-5- il) biphenyl to) 5- (5'-Chloro-2-methoxybiphenyl-3-yl) -1H-tetrazol

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 5- (3-bromophenyl) -1H-tetrazol instead of the compound of 1a), the title compound was prepared (1.36 g; 100%) in the form of a white solid. 1 H NMR (300 MHz, d6 -DMSO) δ 8.16 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.7 (d, J = 6.6 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.48 (m, 2H), 7.2 (d, J = 9.1 Hz, 1H), 3.8 (s, 3H), MS (ES) m / z 287 [M + H].

b) 5- (5'-Chloro-2-hydroxybiphenyl-3-yl) -1H-tetrazol

Following the procedure of Example 3d), with the exception that the compound of 12a) was used instead of 3c compounds), the title compound was prepared. MS (ES) m / z 250 [M + H].

C) 5- (5'-Chloro-2'-hydroxybiphenyl-3'-nitro-3-yl) -1H-tetrazol

Following the procedure of Example 7c), with the exception that the compound of 12b) was used instead of compound of 7c), the title compound was prepared in the form of a yellow solid (0.5 g; 84%,). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.2 (s, 1H), 8.1 (d, J = 5.9 Hz, 1H), 8.09 (d, J = 7.4 Hz, 1H), 7.8 (d, J = 2.7 Hz, 1H), 7.75 (m, 2H), MS (ES) m / z 295 [M + H].

d) 3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3' - (tetrazol-5- il) biphenyl

Following the procedure of Example 1c), with the exception that the compound of 12c) was used instead of compound of I b), the crude product was isolated. A suspension of crude product (0.0015 mol) in ac hydrochloric acid. 1 M (25.0 ml) was cooled to 5 ° C and then treated dropwise with a solution of sodium nitrite (0.11 g; 0.0015 mol) in water (5.0 ml). Mix yellow color was stirred at 5 ° C for another 10 min and then treated in one portion with the compound of Example 1d) (0.34 g, 0.0015 mol) followed by the addition in portions of acid carbonate sodium and ethanol ensuring that the final pH of the reaction mixture out of about 7-8. Then the solution Red color was stirred at room temperature for 24 h. The mixture was filtered to give a red solid that was suspended in water (50.0 ml) and then acidified with hydrochloric acid concentrated. Filtration produced the title compound (0.14 g; 20%) in the form of a powder. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s, 1H), 9.8 (s, 1H), 8.26 (s, 1H), 8.1 (d, J = 1.5 Hz, 1H), 7.75 (m, 3H), 7.6 (d, J = 2.2 Hz, 1H), 7.2 (m, 3H), 2.35 (s, 3H), 2.25 (d, J = 2.2 Hz, 6H).

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Example 13 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -5'-fluoro-2'-hydroxybiphenyl-3 -carboxylic a) Acid 5'-fluoro-2'-methoxybiphenyl-3-carboxylic acid

Following the procedure of Example 1 b), with the exception that acid was used 5-fluoro-2-methoxyphenylboronic  instead of 4-carboxyphenylboronic acid, and was used 3-bromophenyl carboxylic acid instead of the compound from 1a), the title compound (1.59 g; 100%) was prepared as of a white solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.26 (s, 1H), 8.1 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.10 (dd, J = 9.0, 3.4 Hz, 1H), 7.05 (dd, J = 9.0, 3.4 Hz 1H), 6.95 (dd, J = 9.0, 4.6 Hz, 1H), 3.8 (s, 3H).

b) Acid 5'-fluoro-2'-hydroxybiphenyl-3-carboxylic

Following the procedure of Example 1b), with the exception that the compound of Example 13a) was used instead of compound of Example 1a), the title compound was prepared in form of a white solid (1.0 g, 71%). 1 H NMR (300 MHz, d 6 -DMSO) δ 9.7 (s, 1H), 8.19 (s, 1H), 7.91 (d, J = 6.9 Hz, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 9.2, 3.4 Hz 1H), 6.9 (dd, J = 9.2, 4.6 Hz, 1H).

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c) Acid 5'-fluoro-2'-hydroxy-3'-aminobiphenyl-3-carboxylic acid

Following the procedure of Example 7c), with the exception that the compound of Example 13b) was used instead of compound of Example 7b). The crude product was isolated and then it was dissolved in 10 ml of ethanol, treated with 5% Pd / C and stirred at 344.74 kPa (50 psi) hydrogen for 1.5 hours. After the concentration, the title compound was prepared as a dark colored gum (0.047 g, 36%, two stages). MS (ES) m / z 248 [M + H].

d) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -5'-fluoro-2'-hydroxybiphenyl-3 -carboxylic

Following the procedure of Example 1e), with the exception that the compound of Example 13c) was used instead of compound of Example 1c), the title compound was prepared in form of a solid (0.03 g, 41%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.28 (s, 1H), 7.91 (m, 4H), 7.59 (t, J = 8.0, 1H), 7.19 (m, 2H), 6.9 (dd, J = 9.2, 3.4 Hz, 1H), 2.35 (s, 1H), 2.2 (s, 3H), 2.18 (s, 3H). MS (ES) m / z 461 [M + H].

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Example 14 Acid 7 - ({N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxyphenyl) quinolin-4 [1H] -one-3-carboxylic a) Acid 7- (5-Chloro-2-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used acid 7-Bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid instead of the compound of 1a), the crude product was isolated. He Previous crude product was treated with glacial acetic acid (25.0 ml) and hydrobromic acid ac. 48% (25.0 ml), stirred and heated at reflux for 5 h.

The mixture was cooled and filtered to produce the title compound (1.85 g; 73%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.4 (d, J = 6.5 Hz, 1H), 10.2 (s, 1H), 8.9 (d, J = 6.8 Hz, 1H), 8.3 (d, J = 8.6 Hz, 1H), 8.06 (s, 1H), 7.8 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 7.7, 2.6 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H).

b) Acid 7- (5-Chloro-2-hydroxy-3-nitrophenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic

Following the procedure of Example 7c), with the exception that the compound of 14a) was used instead of compound of 7b), the title compound was prepared (0.84 g; 90%) in the form of a powder. MS (ES) m / z 361 [M + H].

c) Acid 7 - ({N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxyphenyl) quinolin-4 [1H] -one-3-carboxylic

Following the procedure of Example 1c), with the exception that the compound of 14b) was used instead of compound of 1b), the crude product was isolated. After, following the procedure of example 1e), with the exception that the previous crude product instead of the 1c compound) and was used 1- (3,4-dimethylphenyl) -3-methyl-3-pyrazolin-5-one  instead of the 1d compound), the title compound was prepared in form of a solid (0.04 g; 8%,). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 15.3 (s, 1H), 13.8 (s, 1H), 13.4 (s, 1H), 9.98 (s, 1H), 8.92 (d, J = 6.6 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.99 (s, 1H), 7.77 (m, 4H), 7.15 (m, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H). MS (ES) m / z 510 [M + H].

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Example 15 7 - ({N '- [1- (4- tert- Butyl-phenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxyphenyl) quinolin-4 [ 1H] -one-3-carboxylic

Following the procedure of Example 14, with the exception that the compounds of 4a) were used instead of 1d compound), the title compound was prepared (0.24 g, 40%) in the form of a solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.68 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.68 (m, 5H), 7.48 (d, J = 8.7 Hz, 1H), 7.10 (m, 2H), 2.4 (s, 3H), 1.34 (s, 9H).

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Example 16 Acid 3-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- carboxylic

Following the procedure of Example 7, with the except that the compounds of 1d) were used instead of compound of 4a), the title compound was prepared (0.51 g, 78%) in the form of a solid. 1 H NMR (300 MHz, CDCl 3) δ 9.16 (s, 1H), 8.9 (s, 1H), 8.5 (s, 1H), 7.7 (t, J = 4.8 Hz, 1H), 7.6 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8, 1 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 2.4 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), MS (M) z / 444 [M + H].

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Example 17 Acid 3-aza-3 '- (N' - [1 {3-methyl- [4- (1-methyl ethyl) phenyl] -5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino) -2'-hydroxybiphenyl -5-carboxylic to) 1- (4-Isopropylphenyl) -3-methyl-3-pyrazolin-5-one

Following the procedure of example 1d), with the exception that hydrochloride was used 4-Isopropylphenylhydrazine instead of hydrochloride 3,4-dimethylphenylhydrazine, the compound was prepared of the title (3.2 g; 89%). 1 H NMR (300 MHz, CDCl 3) δ 7.7 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 3.45 (s, 2H), 2.2 (s, 3H), 2.1 (s, 3H), MS (ES) m / z 217 [M + H].

b) Acid 3-aza-3 '- (N' - [1- {3-methyl- [4- (1-methyl ethyl) phenyl] -5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino) -2'- hydroxybiphenyl-5-carboxylic

Following the procedure of Example 7, with the except that the compounds of 17a) were used instead of 4a compound), the title compound was prepared (0.16 g, 23%) in the form of a solid. 1 H NMR (300 MHz, CDCl 3) δ 13.7 (s at, 1H), 9.9 (s, 1H), 9.0 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.2 (m. 2H), 2.35 (s, 3H), 1.2 (d, J = 6.7 Hz, 6H), MS (EN) m / z 458 [M + H].

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Example 18 3-aza-3 '- {N' - [1- (3- tert -butylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- acid carboxylic a) 1- (3- tert- Butylphenyl) -3-methyl-3-pyrazolin-5-one

Following the procedure of example 1d), with the exception that 3- tert- butylphenylhydrazine hydrochloride was used instead of 3,4-dimethylphenylhydrazine hydrochloride, the title compound (0.8 g; 70%) was prepared. 1 H NMR (300 MHz, CDCl 3) δ 7.9 (s, 1H), 7.68 (d, J = 2.6 Hz, 1H), 7.24 (m, 3H) , 3.4 (s, 2H), 2.2 (s, 3H), 1.33 (s, 9H).

b) 3-aza-3 '- {N' - [1- (3- tert -butylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- acid 5-carboxylic

Following the procedure of Example 7, with the except that the compounds of 18a) were used instead of compound of 4a), the title compound (0.2 g, 25%) was prepared in solid form. 1 H NMR (300 MHz, CDCl 3) δ 13.7 (s a, 1H), 9.9 (s, 1H), 9.0 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 8.0 (s, 1H), 7.79 (dd, J = 8.5 Hz, 1.9 Hz, 2H), 7.4 (t, J = 7.9 Hz, 1H), 7.28 (m, 3H), 2.35 (s, 3H), 1.3 (s, 9H), MS (ES) m / z 472 [M + H].

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Example 19 Acid 5'-chloro-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic a) Acid 5'-Chloro-2'-methoxybiphenyl) -3-carboxylic

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 3-Bromocarboxylic acid instead of the compound of 1a), the title compound (2.82 g; 75%) was prepared as A white powder. 1 H NMR (300 MHz, CDCl 3) δ 8.21 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.32 (dd, J = 9.0 Hz, 4.0 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H).

b) Acid 5'-Chloro-2'-hydroxyphenyl-3-carboxylic

Following the procedure of Example 3d), with the exception that the compound of 20a) was used instead of 3c compounds), the title compound was prepared (2.33 g; 90%) in the form of a solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 10.19 (s, 1H), 8.15 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.25 (dd, J = 9.0 Hz, 3.4 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H).

c) Acid 5'-Chloro-2'-hydroxy-3'-nitrophenyl-3-carboxylic acid

Following the procedure of example 7c), with the exception that the compound of 20b) was used instead of compound of 7b), the title compound was prepared in the form of a yellow powder (0.4 g, 68%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 10.8 (s, 1H), 8.14 (s, 1H), 8.1 (d, J = 3.4 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.79 (m, 2H), 7.63 (t, J = 8.1 Hz, 1H).

d) Acid 5'-chloro-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic

Following the procedure of example 8, with the except that example compound 20c) was used instead of example compound 6c), the title compound was prepared in solid form. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 10.0 (s, 1H), 8.14 (s, 1H), 8.0 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.64 (m, 4H), 7.22 (d, J = 8.1 Hz, 1H), 7.2 (s, 1H), 2.33 (s, 1H), 2.28 (s, 1H), 2.25 (s, 1 H), MS (ES) m / z 477 [M + H].

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Example 20 Acid preparation 3 '- {N' - [1- (3,4-dimethylphenyl) -3,5-dioxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

An acid suspension 3-amino-2-hydroxybiphenyl-3'-carboxylic acid, hydrochloride salt (0.057 g; 0.0002 mol) in hydrochloric acid ac. 1 m (3.0 ml) was cooled to 5 ° C and then treated dropwise with a sodium nitrite solution (0.017 g; 0.00024 mol) in water (2.0 ml). The yellow mixture was stirred at 5 ° C for a further 10 min and then it was treated with 1- (3,4-dimethylphenyl) pyrazolidine-3,5-dione (44 mg; 0.0002 mol), followed by the addition in portions of a sodium carbonate solution ensuring that the final pH of the reaction mixture outside about 7-8, and ethanol (3.0 ml) to improve solubility. Then the solution of Red color was stirred at room temperature for 24 h.

The mixture was diluted with water, acidified with ac hydrochloric acid 1 M, stirred for a further 30 minutes and was filtered to give a brown solid that was washed with water to produce the title compound (0.04 g; 42%) as a powder brown, MS m / e 445 [M + H] +.

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Example 21 Acid preparation 3 '- {N' - [1- (2-Ethoxy-2-oxoethyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 3-Methyl-3-pyrazolin-5-one-1-acetate of ethyl

Following the procedure of Example 1d), with the exception that hydrochloride was used hydrazino-ethyl acetate instead of 3,4-dimethylphenylhydrazine, the compound was prepared of the title (1.12 g; 20%) in the form of a yellow solid pale, 1 H NMR (300 MHz, d 6 -DMSO) δ 10.90 (s, 1H), 5.15 (s, 1H), 4.58 (s, 2H), 4.13 (c, J = 7.1 Hz, 2H), 2.01 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).

b) Acid 3 '- {N' - [1- (2-Ethoxy-2-oxoethyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Ac. Sodium nitrite ac. Was added dropwise. 0.23 M (1 ml, 0.23 mmol) to a stirred suspension of acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid,  hydrochloride salt (0.050 g, 0.188 mmol) in aq hydrochloric acid. 1 m (2.5 ml) at 5 ° C. The mixture was stirred 10 min and a solution was added. from 3-methyl-3-pyrazolin-5-one-1-acetate of ethyl (0.035 g, 0.188 mmol) in ethanol (3 ml). Was added sodium carbonate until the pH was 8 and the reaction was allowed to warm to room temperature and then stirred for 18 h and poured into acetic acid ac. (0.5 M, 50 ml). The mixture is extracted (2 x 10 ml of ethyl acetate) and the extracts were washed with water (2 x 5 ml) and brine (5 ml) and dried (MgSO4). He solvent was removed under reduced pressure and the residue was purified by preparative hplc (ODS-silica, acetonitrile al 10-90% / water-0.1% TFA) for produce the title compound (0.024 g; 30%) in the form of a solid orange. MS (ES) m / z 425 (M + H) +.

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Example 22 3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-4' - (tetrazol-5- il) biphenyl

Following the procedure of Example 25d), prepared the title compound as a solid (0.08 g, 10%) after purification by preparative hplc (ODS-silica, acetonitrile al 10-90% / water-0.1% TFA) 1 H NMR (300 MHz, d6 -DMSO) δ 13.7 (s at, 1H), 9.7 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.73 (m, 2H), 7.64 (dd, J = 2.3 Hz, 8.2 Hz, 1H), 7.24 (m, 3H), 2.35 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). MS (ES) m / z 467 [M + H].

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Example 23 Preparation of 3 '- (N' - {1- [2- (N- tert- butyl) amino-2-oxoethyl] -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino) -2'-hydroxybiphenyl-3-carboxylic a) 3-Methyl-N- tert -butyl-3-pyrazolin-5-one-1-acetamide

A solution of trimethylaluminum in toluene (2 M, 1 ml, 2.00 mmol) was injected into an ice cold stirred solution of tert- butylamine (0.210 ml, 2.00 mmol) in dichloromethane (3 ml) under argon . After 5 min, 3-methyl-3-pyrazolin-5-one-1-ethyl acetate (0.092 g, 0.500 mmol) was added in one portion and the mixture was stirred at room temperature for 24 h. Water (0.67 ml, 37.2 mmol) was added dropwise and stirring was continued until the amorphous solid separated. Ethyl acetate (5 ml) was added followed by an excess of sodium acid carbonate and the mixture was stirred for 15 min and then filtered through a bed of Celite®. The cake was repeatedly washed with ethyl acetate and the solvent was removed from the filtrate under reduced pressure to give the title compound (0.106 g; 100%) as an amorphous solid suitable for use in the next step. 1 H NMR (300 MHz, d 6 -DMSO) δ 7.52 (s, 1H), 4.95 (s, 1H), 4.21 (s, 2H), 1.98 ( s, 3H), 1.24 (s, 9H).

b) 3 '- (N' - {1- [2- (N- tert- butyl) amino-2-oxoethyl] -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino) acid -2'-hydroxybiphenyl-3-carboxylic

Following the procedure of Example 21b), with the exception that 3-methyl-N- tert- butyl-3-pyrazolin-5-one-1-acetamide was used instead of 3-methyl-3-pyrazolin-5-one -1-ethyl acetate, the title compound (0.05 g; 29%) was prepared as an orange solid. MS (ES) m / z 452 (M + H) +.

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Example 24 Acid preparation 3 '- {N' - [3-Chloro-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2-Acetyl (3,4-dimethylphenyl) hydrazine

It was prepared according to the procedure of E.C. Taylor and J. S. Hinkle, J. Org. Chem., 1987, 52 (18), 4107.

b) 1- (3,4-Dimethylphenyl) pyrazolidine-3,5-dione

It was prepared according to Chemical Abstracts 1964, 60, 15880 (M Yokoyama, T Kurihara and T Takahashi, Japan 2872 (1964).

C) 1- (3,4-Dimethylphenyl) -5-chloro-3-oxo-pyrazolidine

It was prepared according to Chemical Abstracts 1964, 60, 15880 (M Yokoyama, T Kurihara and T Takahashi, Japan 2872 (1964).

The two products, 1- (3,4-dimethylphenyl) -5-chloro-3-oxo-pyrazolidine Y 1- (3,4-dimethylphenyl) -3,5-dichloropyrazolidine  they were separated by flash chromatography (silica gel, from dichloromethane-hexane to 1% methanol in dichloromethane). MS m / e 241 [M + H] + (dichloro derivative) and MS m / e 223 [M + H] + (monochloric derivative).

d) Acid 3 '- {N' - [3-Chloro-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

An acid suspension 3-amino-2-hydroxybiphenyl-3'-carboxylic acid, hydrochloride salt (0.2 g; 0.00076 mol) in ac hydrochloric acid. 1 m (3.0 ml) and tetrahydrofuran (3.0 ml) was cooled to 5 ° C and then treated dropwise with a solution of sodium nitrite (0.057 g; 0.00083 mol) in water (1.0 ml). The yellow mixture was stirred at 5 ° C for a further 10 min and then treated with a solution of 1- (3,4-dimethylphenyl) -5-chloro-3-oxo-pyrazolidine  (0.168 g; 0.00076 mol) in tetrahydrofuran (3.0 ml), followed by portionwise addition of a sodium acid carbonate solution ensuring that the final pH of the reaction mixture was approximately 7-8. Then the color solution Red was stirred at room temperature for 24 h.

The mixture was diluted with water and acidified with ac hydrochloric acid 1 M, stirred for a further 30 minutes and was filtered to give a brown solid that was washed with water to produce the title compound (0.3 g; 85%) in the form of a powder brown, m.p. = 210 ° C (dec.). MS m / e 463 [M + H] +.

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Example 25 5-Chloro-3- {N '- [{1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-4'- (tetrazol-5-yl) biphenyl to) 5- (5'-Chloro-2-methoxybiphenyl-4-yl) -1H-tetrazol

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 5- (4-bromophenyl) -1H-tetrazol instead of the compound of 1a), the title compound was prepared (1.4 g; 100%) in the form of a solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.1 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.4 (m, 2H), 7.15 (d, J = 9.0 Hz, 1H), 3.8 (s, 3H).

b) 5- (5'-Chloro-2-hydroxybiphenyl-4-yl) -1H-tetrazol

Following the procedure of Example 3d), with the exception that the compound of 29a) was used instead of 3c compounds), the title compound was prepared. 1 H NMR (300 MHz, d 6 -DMSO) δ 10.1 (s, 1H), 8.1 (d, J = 6.6 Hz, 2H), 7.8 (d, J = 6.6 Hz, 2H), 7.38 (d, J = 2.7 Hz, 1H), 7.2 (dd, J = 2.7 Hz, 8.7 Hz, 1H).

C) 5- (5'-Chloro-2'-hydroxybiphenyl-3'-nitro-3-yl) -1H-tetrazol

Following the procedure of Example 1a), with the exception that the compound of 29b) was used instead of 3-Bromophenol, the title compound was prepared in form of a solid (0.95 g; 86%,). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.12 (m, 3H), 7.8 (m, 3H).

d) 5-Chloro-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino [-2-hydroxy-4' - ( tetrazol-5-yl) biphenyl

Following the procedure of example 1c), with the exception that the compound of 29c) was used instead of compound of example 1b), a mixture of products (1: 1) of 5- (5'-Chloro-2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol  Y 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol. MS m / e 254 and 288 [M + H] +.

Following the procedure of Example 1e), with the exception that the previous product mix was used instead of the compound of 1c), the title compound was prepared in the form of a solid (0.12 g, 14%) after hplc purification preparative (ODS-silica, acetonitrile al 10-90% / water-0.1% TFA) 1 H NMR  (300 MHz, d6 -DMSO) δ 13.6 (s, 1H), 8.15 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 2.35 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). MS (ES) m / z 501 [M + H].

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Example 26 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,5-dicarboxylic acid a) Acid 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3,5-dicarboxylic acid

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 5-Bromo-isophthalic acid instead of compound of 1a), the crude product was isolated and treated with glacial acetic acid (25.0 ml) and 48% aqueous hydrobromic acid (25.0 ml), stirred and heated at reflux for 5 h. The mixture is cooled and filtered to produce the crude compound as a powder Then, following the procedure of Example 1a), with the exception that the previous raw compound was used instead of 3-Bromophenol, the title compound was prepared in form of a solid (0.58 g; 33%, three stages) in the form of a solid. 1 H NMR (300 MHz, d 6 -DMSO) δ  8.5 (t, J = 1.6 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.2 (d, J = 1.6 Hz, 2H), 8.1 (d, J = 2.7 Hz, 1H), 7.8 (d, J = 2.7 Hz, 1H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,5-dicarboxylic acid

Following the procedure of Example 12d), with the exception that the compound of 30c) was used instead of compound of 12c), the title compound was prepared in the form of a solid. 1 H NMR (300 MHz, d 6 -DMSO) δ 8.5 (s, 1H), 8.33 (s, 2H), 7.76 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.24 (m, 3H), 2.35 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). EM (EN) m / z 487 [M + H].

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Example 27 Acid 3-aza-3 '- {N' - {1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 ' -methylbiphenyl-5-carboxylic a) Acid 5-methyl-2-methoxyphenylboronic

To the THF solution of 2-Bromo-1-methoxy-4-methylbenzene (1.39 g, 15 mmol) at -78 ° C under nitrogen atmosphere n-butyllithium (15 mmol) was added dropwise. After stirring at -78 ° C for one hour, the solution was added to trimethylborate (15 mmol) in THF (100 ml). The mixture of reaction was heated to room temperature and continuously stirred for four hours before pouring into 3 N hydrochloride (125 ml) and It was then extracted three times with ethyl acetate. Extracts organic were combined, dried over magnesium and concentrated  to give a yellow-white solid (2.2 g, 89%). 1 H NMR (300 MHz, d 6 -DMSO) δ 7.6 (s, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.19 (dd, J = 8.4 Hz, 2.3 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 2.2 (s, 3H).

b) Acid 5- (2-Methoxy-5-methylphenyl) -nicotinic

Following the procedure of Example 7a), with the exception that the compound of 31 a) was used instead of acid 4-carboxyphenylboronic, the compound of the title in the form of a solid (2.88 g, 90%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 9.0 (s, 1H), 8.8 (s, 1H), 8.3 (t, J = 2.0 Hz, 1H), 7.2 (m, 2H), 7.08 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H), 2.31 (s, 3H).

c) Acid 5- (2-hydroxy-5-methylphenyl) -nicotinic

Following the procedure of Example 3d), with the exception that the compound of 31b) was used instead of 3c compounds), the title compound was prepared. 1 H NMR (300 MHz, d 6 -DMSO) δ 8.98 (s, 1H), 8.93 (s, 1H), 8.4 (t, J = 2.1 Hz, 1H), 7.2 (s, 1H), 7.0 (d, J = 8.5 Hz, 1H), 6.9 (d, J = 8.9 Hz, 1H), 2.31 (s, 3H).

d) Acid 5- (2-Methoxy-5-methyl-3-nitrophenyl) -nicotinic

Following the procedure of Example 7c), with the exception that the compound of 31c) was used instead of 7c compound), the title compound was prepared (0.7 g; 31%). 1 H NMR (300 MHz, d 6 -DMSO) δ 9.0 (s, 1H), 8.94 (s, 1H), 8.4 (t, J = 2.1 Hz, 1H), 7.9 (s, 1H), 7.68 (s, 1H), 2.36 (s, 3H).

e) Acid 3-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 ' -methyl-biphenyl-5-carboxylic

Following the procedure of Example 7d), with the exception that the compound of 31d) was used instead of acid 6- (5-Chloro-2-hydroxy-3-nitrophenyl) -pyridine-2-carboxylic acid and the compound of 1d) was used instead of the compound of 4a), prepared the title compound as a solid (0.66 g, 90%). 1 H NMR (300 MHz, CDCl 3) δ 9.14 (s, 1H), 8.9 (s, 1H), 8.6 (s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.9 (s, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H).

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Example 28 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-4-carboxylic acid a) Acid 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-4-carboxylic

Following the procedure of Example 7a), 7b) and 7c), with the exception that acid was used 4-Bromophenylcarboxylic instead of acid 5-bromonicotinic, the compound of the title in the form of a solid (1.0 g, 77%, three stages). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.1 (d, J = 2.7 Hz, 1H), 8.0 (d, J = 6.6 Hz, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.67 (d, J = 6.6 Hz, 1H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-4-carboxylic acid

Following the procedure of Example 7d), with the exception that the compound of 32a) was used instead of acid 6- (5-Chloro-2-hydroxy-3-nitrophenyl) -pyridine-2-carboxylic acid and the compound of 1d) instead of the compound of 4a), the title compound in the form of an orange solid (0.23 g, 24%) 1 H NMR (300 MHz, d 6 -DMSO) δ 13.7 (s, 1H), 12.9 (s, 1H), 9.7 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.69 (m, 3H), 7.65 (d, J = 8.1 Hz, 1H), 7.18 (m, 3H), 2.33 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). MS (ES) m / z 442 [M + H].

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Example 29 Acid preparation 3 '- {N' - [1-3,4-dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 1- (3,4-Dimethylphenyl) -3-methoxy-3-pyrazolin-5-one

A solution of 1- (3,4-dimethylphenyl) pyrazolidine-3,5-dione (0.675 g; 0.0033 mol) in methanol (40.0 ml) was treated with acid sulfuric conc. (10 drops), stirred and heated to reflux for 24 h

Water (20.0 ml) was added and the mixture was evaporated. The residue was triturated with water to produce the compound of title (0.428 g; 60%) in the form of an orange powder. The 1 H NMR (300 MHz, d 6 -DMSO) revealed a approximately 1: 1 mixture of tautomers of hydroxypyrazole: pyrazolone. MS (ES) m / z 219 [M + H].

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of Example 1e), with the exception that the compound of Example 3e) was used instead of compound of Example 1c) and the compound of Example 29a) instead of compound of Example 1d), the title compound was prepared (0.142 g; 41%) in the form of an orange solid. 1 H NMR (300 MHz, d 6 -DMSO) δ 13.7 (s, 1H), 13.1 (s a, 1H), 9.71 (s, 1H), 8.14 (s, 1H), 7.97 (dd, J = 7.8, 1.4 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.72 (s, 1H), 7.65-7.60 (m, 3H), 7.22-7.11 (m, 3H), 4.06 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H); Anal. (C 25 H 22 N 4 O 5 {0.66 H 2 O) calc .: C, 63.82; H, 5.00; N, 11.91, found: C, 63.53; H, 4.95; N, 11.49.

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Example 30 Acid preparation 3 '- {N' - [1- (4-methoxyphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 1- (4-Methoxyphenyl) -3-methyl-3-pyrazolin-5-one

Following the procedure of Example 1d), with the exception that hydrochloride was used 4-methoxyphenylhydrazine instead of hydrochloride 3,4-dimethylphenylhydrazine, the compound was prepared of the title (2.2 g; 27%) in the form of a cream-colored powder. 1 H NMR (300 MHz, d 6 -DMSO) δ 11.3 (s, 1H), 7.57 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 5.32 (s at, 1H), 3.77 (s, 3H), 2.10 (s, 3H).

b) Acid 3 '- {N' - [1- (4-methoxyphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of Example 1e), with the exception that the compound of Example 3e) was used instead of compound of Example 1c) and the compound of Example 30a) instead of compound of Example 1d) and washing the crude product with chloroform, the title compound (0.146 g; 49%) was prepared in Shape of an orange solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s, 1H), 13.1 (s a, 1H), 9.70 (s, 1H), 8.14 4 (t, J = 1.4 Hz, 1H), 7.97 (dt, J = 7.9, 1.4 Hz, 1H), 7.84-7.60 (m, 5H), 7.19-7.15 (m, 2H), 7.04 (d, J = 9.1 Hz, 2H), 3.79 (s, 3H), 2.34 (s, 3H); Anal. (C 24 H 20 N 4 O 5 .0.5 H2O; 0.5 CHCl3) calc .: C, 57.35; H, 4.22; N, 10.91, Found: C, 57.69; H, 4.35; N, 10.80,

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Example 31 3- {N '- [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-trifluoromethanesulfonamidobiphenyl to) N- (2'-Methoxy-3'-nitrobiphenyl-3-yl) -acetamide

Following the procedure of example 1b), with the exception that acid was used 3-acetamidobenzeneboronic instead of the compound of 4-carboxyphenylboronic acid and 1-Bromo-2-methoxy-3-nitrobenzene instead of the compound of example 1a), the compound of the title in the form of a solid. (1.16 g, 98%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 7.73 (dd, J = 1.7 Hz, 7.5 Hz, 1H), 7.68 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 1.7 Hz, 7.5 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 3.52 (s, 3H), 2.10 (s, 3H).

b) Hydrochloride salt of 3'-amino-3-nitrobiphenyl-2-ol

Following the procedure in example 3d), with the exception that the compound of 31a) was used instead of compound of 3c), the title compound was prepared in the form of a solid (0.7 g, 56%). MS (ES) m / z 231 [M + H].

C) 1,1,1-trifluoro-N- (2'-hydroxy-3'-nitrobiphenyl-3-yl) -methanesulfonamide

Example compound 31a) in ethyl acetate was added to a 5% solution of sodium hydroxy and stirred for 10 min, and then the aqueous solution was neutralized with 3N HCl at pH = 7 and extracted with ethyl acetate. After the concentration, 0.25 g of neutral compound were obtained.

The neutral compound (0.25 g) was dissolved in chloroform (25 ml), treated with triflic anhydride at 0 ° C and stirred at room temperature for 1 hour. Hydrochloride 3 was added N to adjust the pH to 4 and the mixture was extracted with acetate ethyl. The organic phases were combined, dried (MgSO4) and concentrated to give a yellow solid (0.39 g, 100%) MS (ES) m / z 340 [M + H].

d) 3- {N '- [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino-2-hydroxy-3'-trifluoromethanesulfonamidobiphenyl

Following the procedure of example 7d), with the exception that the compound of example 31b) was used instead of the compound of example 7c) and 1- (3,4-dimethylphenyl) -3-methyl-3-pyrazolin-5- one instead of 1- (4- tert- butylphenyl) -3-methyl-3-pyrazolin-5-one, the title compound was prepared as a solid (34%). MS (ES) m / z 546 [M + H].

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Example 32 Acid preparation 3 '- {N' - [1- (3,4-dichlorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 1- (3,4-Dichlorophenyl) -3-methyl-3-pyrazolin-5-one

Following the procedure of Example 1d), with the exception that hydrochloride was used 3,4-Dichlorophenylhydrazine instead of hydrochloride 3,4-dimethylphenylhydrazine, the compound was prepared of the title (7.5 g; 65%) in the form of a cream-colored powder. 1 H NMR (300 MHz, d 6 -DMSO) δ 8.02 (d, J = 2.4 Hz, 1H), 7.8 (dd, J = 8.9, 2.5 Hz, 1H), 7.7 (d, J = 8.9, 1H), 5.31 (s, 1H), 2.1 (s, 3H).

b) Acid 3 '- {N' - [1- (3,4-dichlorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of Example 1e), with the exception that the compound of Example 3e) was used instead of compound of Example 1c) and the compound of Example 37a) instead of compound of Example 1d) and washing the crude product with chloroform, the title compound (0.253 g; 78%) was prepared in Shape of an orange solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.6 (s, 1H), 13.1 (s, 1H), 9.76 (s, 1H), 8.13 (m, 2H), 7.97 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.68-7.60 (m, 3H), 7.17-7.09 (m, 2H), 2.31 (s, 3H); Anal. (C 23 H 16 Cl 2 N 4 O 4 {0.5 H 2 O) calc .: C, 56.11; H, 3.48; N, 11.38, found: C, 56.14; H, 3.47; N, 11.24.

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Example 33 Acid preparation 3 '- {N' - [3-methyl-5-oxo-1- (3-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino] -2'-hydroxy-biphenyl-3-carboxylic acid to) 1- (3-Trifluoromethylphenyl) -3-methyl-3-pyrazolin-5-one

Following the procedure of Example 1d), with the exception that hydrochloride was used 3-Trifuoromethylphenylhydrazine instead of hydrochloride of 3,4-dimethylphenylhydrazine, the title compound (5.1 g; 91%). 1 H NMR (300 MHz, CDCl 3) δ 8.17 (s, 1H), 8.1 (d, J = 7.3 Hz, 1H), 7.5 (t, J = 7.7, 1H), 7.45 (d, J = 7.7, 1H), 3.47 (s, 2H), 2.2 (s, 3H).

b) Acid 3 '- {N' - [3-methyl-5-oxo-1- (3-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene} hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of Example 1e), with the exception that the compound of Example 3e) was used instead of compound of Example 1c) and the compound of Example 38a) instead of compound of Example 1d) and washing the crude product with chloroform, the title compound (0.241 g; 66%) was prepared in Shape of an orange solid. MS (ES) m / z 483 (M + H) +.

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Example 34 Acid 8- {N '- [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} quinolin-4 [1 H] -one-3-carboxylic acid a) Acid 8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic

To the suspension of 2-nitroaniline (41.4 g, 0.3 mol) in 200 ml of ether diphenyl was added diethyl acid ether 2-ethoxymethylene-malonic (64.8 g, 0.3 mol). The reaction mixture was heated at reflux for half hour, it was cooled to 70 ° C and poured into hexanes (600 ml). Solid resulting was collected and washed with hexanes to give the product in stupid. The crude compound (49 g, 0.19 mol) was dissolved in NaOH at 10% (1 L) and heated at reflux for two hours. After cooled to 60 ° C, the reaction mixture was quenched with hydrochloride 6 N, the resulting precipitate was collected and washed with water to give the title compound in the form of a brown solid (22.6 g, 47%). 1 H NMR (300 MHz, d 6 -DMSO) δ 12.9 (s, 1H), 8.84 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 8.83 (t, J = 7.9 Hz, 1H), 7.79 (dd, J = 8.0 Hz, 1.5 Hz, 1H).

b) Acid 8-amino-4-oxo-1,4-dihydroquinoline-3-carboxylic

Following the procedure of example 1c), with the exception that the compound of example 34a) was used instead of compound of example 1b), the title compound was prepared in form of a solid (1 g, 51%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 12.7 (s, 1H), 8.7 (s, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.33 (t. J = 7.9 Hz, 1H), 7.12 (d, J = 6.6 Hz, 1H).

c) Acid 8- {N '- [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} quinolin-4 [1 H] -one-3-carboxylic acid

Following the procedure of example 1 e), with the exception that the compound of example 34b) was used instead of compound of example 1c), the title compound was prepared in form of a solid (0.4 g, 83%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.31 (d, J = 8.2 Hz, 1H), 8.2 (d, J = 7.4 Hz, 1H), 8.09 (d, J = 14.9 Hz, 1H), 7.82 (d, J = 14.9 Hz, 1H), 7.6 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.3 Hz), 2.46 (s, 3H), 2.28 (s, 3H), 2.25 (s, 2.25).

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Example 35 Acid preparation 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl-3-carboxylic acid to) 1- (4-Trifluoromethylphenyl) -3-methyl-3-pyrazolin-5-one

Following the procedure of Example 1d), with the exception that hydrochloride was used 4-Trifuoromethylphenylhydrazine instead of hydrochloride of 3,4-dimethylphenylhydrazine, the title compound (2.6 g; 46%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.0 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 5.4 (s, 1H), 2.1 (s, 3H).

b) Acid 3 '- {N' - [3-methyl-5-oxo-1- (3-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of Example 1e), with the exception that the compound of Example 3e) was used instead of compound of Example 1c) and the compound of Example 36a) instead of compound of Example 1d) and washing the crude product with chloroform, the title compound (0.21 g; 58%) was prepared in Shape of an orange solid. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s, 1H), 13.1 (s, 1H), 9.78 (s, 1H), 8.18 (d, J = 8.5 Hz, 2H), 8.14 (s, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.8- (s, 1H), 7.75 (dd, J = 7.3, 2.4, 1H), 7.64 (t, J = 5.5, 1H), 7.2 (m, 2H), 2.37 (s, 3 H).

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Example 36 Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-N-methylcarboxamidolfenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic a) Acid 4- (3-methyl-5-oxo-4,5-dihydropyrazol-1-yl) -benzoic acid

Following the procedure of Example 1d), with the exception that 4-hydrazinobenzoic acid was used instead of hydrochloride 3,4-dimethylphenyl hydrazine, se prepared the title compound (1.91 g; 90%) as a solid. 1 H NMR (300 MHz, d 6 -DMSO) δ 12.9 (s, 1H), 11.1 (s, 1H), 8.07 (d, J = 4.2 Hz, 2H), 7.95 (d, J = 4.2 Hz, 2H), 5.4 (s, 1H), 2.13 (s, 3H).

b) Acid 3'-N '- [3-methyl-5-oxo-1- (4-N-methylcarboxamidolfenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

To the solution in acid DMF 4- (3-methyl-5-oxo-4,5-dihydropyrazol-1-yl) -benzoic acid (0.218 g, 1 mmol), 1-hydroxy-benzotriazole hydrate (0.149 g, 1.1 mmol) and methylamine (1.1 mmol) hydrochloride was added from 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide  (0.211, 1.1 mmol). The reaction mixture was stirred at temperature. ambient for 18 hours. Water was added and the resulting mixture was extracted with ethyl acetate and the extract was dried (MgSO4), filtered and concentrated. The crude product was isolated in the form of a solid. Following the procedure of Example 1e) with the exception that the compound of Example 3e) was used instead of acid 4-amino-3'-hydroxybiphenyl-4-carboxylic acid,  hydrochloride salt and the previous raw product instead of compound of Example 1d), the title compound was prepared in form of a solid (0.056 g, 34%, two stages). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 9.77 (s, 1H), 8.46 (d, J = 4.6 Hz, 1H), 8.14 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.95 (t, J = 7.8 Hz, 2H), 7.85 (d, J = 6.7 Hz, 1H), 7.75 (dd, J = 7.9, 2.6 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.2 (m, 2H), 2.78 (s, 3H), 2.28 (s, 3H). MS (ES) m / z 487 (M + H) +.

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Example 37 N- [1- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-il)  methanoyl] methanesulfonamide to) N- [1- (5'-Chloro-2'-methoxybiphenyl-3-yl) -methanoyl] -methanesulfonamide

Methanesulfonamide (1.74 g, 18.3 mmol) in CH 2 Cl 2 (20 ml) was treated with pyridine (1.44 g, 18.2 mmol) and 3-bromobenzoyl chloride (4.0 g, 9.11 mmol). The reaction mixture was stirred at room temperature for 18 h. Water was added and the organic solution was dried over MgSO4, filtered and concentrated to give the crude product. A solution of the above crude compound (2.85 g, 10.2 mmol), 2-methoxy-5-chlorophenylboronic acid (1.91 g, 10.2 mmol), aq sodium carbonate. 2M (5.1 ml; 10.2 mmol) and tetrakis triphenylphosphine palladium (0) (0.5 g) in 1,4-dioxane (60.0 ml), stirred and refluxed under an atmosphere of nitrogen for 24 h. The reaction mixture was cooled and evaporated and the residue was treated with aq. Hydrochloric acid. 6 M (100 ml). The gray precipitate was filtered and washed well with water and then with diethyl ether to yield the title compound (2.3 g; 88%) as a colorless solid. 1 H NMR (300 MHz, CDCl 3) δ 8.8 (s, 1H), 7.95 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H) , 7.75 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.3 (m, 2H), 6.95 (d, J = 9.0 Hz, 1H), 3.8 (s, 3H), 3.5 (s, 3H).

b) N- [1- (5'-Chloro-2'-hydroxybiphenyl-3-yl) -methanoyl] methanesulfonamide

The compound of example 37a) was dissolved in iodotrimethylsilane (10 ml). The reaction mixture was stirred at room temperature for 18 h and then heated to 60 ° C for 18 h. After cooling to room temperature, it was poured water cooled with ice, which caused precipitation. Solid was collected and further purified by chromatography on SiO 2 (3% MeOH / CH 2 Cl 2). The title compound is prepared in the form of a yellow gum (0.12 g, 30%). 1 H NMR (300 MHz, CDCl 3) δ 8.0 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.6 (t, J = 8.0 Hz, 1H), 7.23 (m, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.9 (d, J = 9.0 Hz, 1H), 3.5 (s, 3H).

C) N- [1- (5'-Chloro-3'-nitro-2'-hydroxybiphenyl-3-yl) -methanoyl] methanesulfonamide

Following the procedure of example 7c), with the exception that example compound 37b) was used instead of example compound 7b), the title compound was prepared in form of a yellow solid (0.1 g, 87%). MS (ES) m / z 371 (M + H) +.

d) N- [1- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-yl) methanoyl] methanesulfonamide

Following the procedure of example 12d), with the exception that example compound 37c) was used instead of example compound 12c) the title compound was prepared in form of a dark colored powder (0.04 g, 48%). MS (ES) m / z 520 (M + H) +.

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Example 38 Acid 3 '- {N' - [3-methyl-5-oxo-1-phenyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic  instead of acid 4'-amino-3'-hydroxybiphenyl-3-carboxylic acid; Y 5-methyl-2-phenyl-2,4-dihydropyrazol-3-one instead of the example compound 1d), the compound of the title in the form of a solid (0.15 g, 65%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 14.9 (s, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.9 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.34 (m, 3H), 7.0 (m, 3H), 2.34 (s, 3H).

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Example 39 Acid 3 '- {N' - [3-methyl-1- (4-methylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic  instead of acid 4'-amino-3'-hydroxybiphenyl-3-carboxylic acid; Y 5-methyl-2-p-tolyl-2,4-dihydropyrazol-3-one instead of the example compound 1d), the compound of the title in the form of a solid (0.11 g, 46%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.19 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.9 (t, J = 8.0 Hz, 1H), 2.34 (s, 3H), 2.23 (s, 3H). MS m / z 429 (M + H) +.

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Example 40 Acid 3 '- {N' - [1- (4-chlorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic  instead of acid 4'-amino-3'-hydroxybiphenyl-3-carboxylic acid; Y 5-methyl-2-chlorophenyl-2,4-dihydropyrazol-3-one  instead of the example compound 1d), the compound of the title in the form of a solid (0.22 g, 88%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.21 (s, 1H), 8.12 (d, J = 8.0 Hz, 2H), 7.9 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.39 (m, 3H), 7.09 (m, 1H), 6.92 (t, J = 8.0 Hz, 1H), 2.34 (s, 3H).

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Example 41 Acid 3 '- {N' - [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (4-Fluorophenyl) -5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that 4-Fluorophenylhydrazine was used instead of 3,4-dimethylphenyl hydrazine, the title compound was prepared as a solid (3.0 g, 64%). MS (ES) m / z
193 (M + H) +.

b) Acid 3 '- {N' - [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol  instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt and the compound of example 45a) instead of example compound 1d), the title compound was prepared (0.16 g, 59%). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.25 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.75 (dd, J = 2.1 Hz, 8.2 Hz, 2H), 7.75 (m, 3H), 7.25 (m, 4H), 2.34 (s, 3H). EM (ES) m / z 457 (M + H) +.

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Example 42 Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 5-methyl-2- (4-trifluoromethoxyphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that it was used 5-methyl-2- (4-trifluoromethoxyphenylhydrazine  instead of 3,4-dimethylphenylhydrazine, the title compound as a solid (2.0 g, 49%). 1 H NMR (300 MHz, d 6 -DMSO) δ 7.85 (d, J = 9.1 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 5.39 (s, 1H), 2.12 (s, 3H). MS (ES) m / z 259 (M + H) +.

b) Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydrobiphenyl-3-carboxylic  instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt and the compound of example 49aa) instead of example compound 1d), the title compound was prepared (0.185 g, 60%). 1 H NMR (300 MHz, d 6 -DMSO) δ 13.7 (s a, 1H), 13.1 (s a, 1H), 9.76 (s a, 1H), 8.1 (s, 1H), 8.05 (d, J = 9, 1 Hz, 2H), 7.97 (d, J = 7.7 Hz, 1H), 7.8 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.65 (t, J = 8.7 Hz, 1H), 7.47 (d, J = 9 Hz, 2H), 7.18 (m, 2H), 2.35 (s, 3H). MS (ES) m / z 499 (M + H) +.

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Example 43 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethoxy-5-oxo-1,5-dihydrorazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid a) Acetic acid, N '- (3,4-dimethylphenyl) hydrazide

3,4-dimethylphenyl was partitioned Hydrazine (5 g, 29 mmol) between sodium hydroxy and ether, the solution of ether was dried and evaporated, giving a solid. The solid dissolved again in ether and treated with acetic anhydride (8 ml, 78 mmol). After stirring at room temperature for 18 hours, the solvent was evaporated to dryness and washed further with ether and hexane to give a solid (3 g, 60%). MS (ES) m / z 179 (M + H) +.

b) 1- (3,4-dimethylphenyl) -pyrazolidine-3,5-dione

The compound of example 47a (3.1 g, 17.7 mmol) in phosphorus trichloride (1.75 ml) it was treated with malonic acid (1.84 g, 17.7 mmol) and heated at 100 ° C until the mixture stopped foaming After cooling to room temperature, the mixture it was dissolved in a sodium bicarbonate solution and extracted with ether. The aqueous solution was acidified with 60% hydrochloride at pH. 6 to 6.5 and then extracted with ethyl acetate (4 times). He Combined extract was dried and evaporated, giving a solid that recrystallized from ethanol to give the title compound. (0.9 g, 26%) 1 H NMR (300 MHz, CDCl 3) δ 7.29 (s, 1H), 7.20 (dd, J = 2.4 Hz, 8.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 3.33 (s, 1H), 2.23 (s, 3H), 2.2 (s, 3H).

C) 2- (3,4-dimethylphenyl) -5-ethoxy-2,4-dihydropyrazol-3-one

To the suspension of the compound of example 43b) (0.8 g, 4 mmol) in ethanol (15 ml) sulfuric acid was added concentrated (0.1 ml, cat.). Then, the reaction mixture is heated to reflux for 48 hours. To the mixture was added potassium carbonate, the solvent was removed under reduced pressure and the residue was purified by column chromatography on SiO2 to produce the title compound (0.25 g; 27%) in the form of a solid. 1 H NMR (300 MHz, CDCl 3) δ 7.65 (s, 1H), 7.57 (dd, J = 2.4 Hz, 8.7 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 4.31 (m, 2H), 3.4 (s, 2H), 2.23 (s, 3H), 2.2 (s, 3H), 1.4 (t, J = 8.6 Hz, 3H).

d) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 4-amino-3'-hydroxybiphenyl-3-carboxylic acid;  hydrochloride salt instead of acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt and the compound of example 43c) instead of example compound 1d), the title compound was prepared (0.015 g, 8%). 1 H NMR (300 MHz, d 6 -DMSO) δ 9.69 (s, 1H), 8.13 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.8 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.65 (m, 3H), 7.2 (m, 2H), 4.4 (m, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.35 (t, J = 8.6 Hz, 3H). EM (ES) m / z 473 (M + H) +.

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Example 44 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethoxy) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic to) 2- (3,4-dimethylphenyl) -5-isopropoxy-2,4-dihydropyrazol-3-one

Following the procedure of example 43c), with The exception that isopropanol was used instead of ethanol, was prepared the title compound as a solid (0.28 g, 28%). 1 H NMR (300 MHz, CDCl3) δ 7.64 (s, 1H), 7.52 (dd, J = 2.4 Hz, 8.7 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 5.1 (m, 1H), 3.4 (s, 2H),  2.23 (s, 3H), 2.2 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethoxy) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic

Following the procedure of example 43d), with the exception that example compound 44a) was used instead of example compound 43c), the title compound was prepared in form of a solid (0.005 g, 5%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 9.65 (s, 1H), 8.10 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.8 (d, J = 8.1 Hz, 1H), 7.6 (s, 1H), 7.6 (m, 3H), 7.15 (m, 2H), 5.18 (m, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 1.46 (s, 3H). 1.44 (s, 3H) MS (ES) m / z 487 (M + H) +.

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Example 45 3 '- {N' - [3- tert -butyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid a) 5- tert -Butyl-2- (3,4-dimethylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that methyl pivaloylacetate was used instead of ethyl acetoacetate, the title compound was prepared as of a solid (4.1 g, 60%). 1 H NMR (300 MHz ,, d_ {6} -DMSO) δ 7.53 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 5.3 (s, 1H), 2.25 (s, 3H), 2.22 (s, 3H), 1.23 (s, 9H).

b) 3 '- {N' - [3- tert -butyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 acid -carboxylic

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydrobiphenyl-3-carboxylic  instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic acid; hydrochloride salt and the compound of example 49aa) instead of example compound 1d), the title compound was prepared (0.06 g, 20%). 1 H NMR (300 MHz, CDCl 3) δ 8.22 (s, 1H), 8.08 (d, J = 6.5 Hz, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.7 (s, 1H), 7.63 (dd, J = 2.6 Hz, 7.1 Hz, 2H), 7.56 (t, J = 7.8, 1H), 7.1 (m, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 1.5 (s, 9H). MS (ES) m / z 485 (M + H) +.

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Example 46 Acid 3 '- {N' - [3-methyl-1- (4-methyl-2,3,5,6-tetrafluorophenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'- hydroxybiphenyl-3-carboxylic acid to) 5-Methyl-2- (2,3,5,6-tetrafluoro-4-methylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that it was used 2,3,5,6-tetrafluoro-4-methylphenyl  hydrazine instead of 3,4-dimethylphenylhydrazine, it prepared the title compound as a solid (1.68 g, 35%) MS (ES) m / z 261 (M + H) +.

b) Acid 3 '- {N' - [3-methyl-1- (4-methyl-2,3,5,6-tetrafluorophenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'- hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic  instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic and the example compound 46a) instead of the example compound 1d), the title compound was prepared (0.07 g, 18%). 1 H NMR (300 MHz, d 6 -DMSO) δ 13.4 (s at, 1H), 9.78 (s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.8 (d, J = 6.4 Hz, 1H), 7.75 (dd, J = 2.2 Hz, 7.4 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.19 (m, 2H), 2.33 (s, 6H).

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Example 47 Acid 3 '- {N' - [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (4-Fluoro-3-methylphenyl) -5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that it was used 4-fluoro-3-methylphenyl hydrazine instead of 3,4-dimethylphenylhydrazine, it prepared the title compound as a solid (1.3 g, 73%). 1 H NMR (300 MHz, d 6 -DMSO) δ 7.63 (m, 1H), 7.55 (m, 1H), 7.17 (t, J = 9.4 Hz, 1H), 5.29 (s at, 1H), 2.26 (s, 3H), 2.09 (s, 3H).

b) Acid 3 '- {N' - [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic  instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic and the example compound 47a) instead of the example compound 1d), the title compound was prepared (0.17 g, 60%). 1 H NMR (300 MHz, d 6 -DMSO) δ 13.7 (s at, 1H), 13.0 (s, 1H), 9.8 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.75 (m, 4H), 7.63 (t, J = 7.7 Hz, 1H), 7.2 (m, 3H), 2.34 (s, 3H), 2.30 (s, 3H). MS (ES) m / z 445 (M + H) +.

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Example 48 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-phenyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of Example 53, with the exception that 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt was used instead of 5- (2'-hydroxybiphenyl-3'-amino-3-yl ) -1H-tetrazole, the title compound was prepared as a solid (0.186 g, 96%). 1 H NMR (300 MHz, d 6 -DMSO) δ 9.80 (sa, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.8 (m, 3H), 7.6 (m, 4H), 7.25 (m, 3H), 2.31 ( s, 3H), 2.26 (s, 3H), MS (ES) m / z
505 (M + H) +.

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Example 49 3- {N'-1 [1- (3,4-dimethylphenyl) -5-oxo-3-phenyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5- ilbiphenyl to) 2- (3,4-dimethylphenyl) -5-phenyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that ethyl benzylacetoacetate was used instead of ethyl acetoacetate, the title compound was prepared as of a solid (2.5 g, 52%). 1 H NMR (300 MHz, CDCl 3) δ 7.84 (m, 2H), 7.75 (s, 1H), 7.47 (dd, J = 3.2 Hz, 6.5 Hz, 1H), 7.45 (m, 3H), 7.15 (d, J = 6.5 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H).

b) 3- {N '- [1- (3,4-dimethylphenyl) -5-oxo-3-phenyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol  instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt and the compound of example 49a) instead of example compound 1d), the title compound was prepared (0.008 g, 4%). MS (ES) m / z 529 (M + H) +.

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Example 50 3- {N '- [1- (3,4-dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino] -2-hydroxy-3'-tetrazol-5-ylbiphenyl to) 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol

Following the procedure of example 1c), with the exception that example compound 12c) was used instead of example compound 1b), the title compound was prepared in form of a solid (1.2 g, 60%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.23 (s, 1H), 8.14 (m, 1H), 7.7 (d, J = 5.6 Hz, 2H), 7.46 (dd, J = 1.6 Hz, 7.9 Hz, 2H), 7.1 (t, J = 7.8 Hz, 1H), MS (ES) m / z 254 (M + H) +.

b) 2- (3,4-dimethylphenyl) -5-methoxy-2,4-dihydropyrazol-3-one

Following the procedure of example 43c), with with the exception that methanol was used instead of ethanol, the title compound as a solid (0.45 g, 56%). MS m / z 219 (M + H) +.

C) 3- {N '- [1- (3,4-dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino [-2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 43d), with the exception that example compound 50a) was used instead of acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, hydrochloride salt, and the compound of example 50b) instead of example compound 47c), the title compound was prepared in solid form. MS (ES) m / z 483 (M + H) +.

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Example 51 3- {N '- [1- (3,4-dimethylphenyl) -3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 50c), with the exception that example compound 43c) was used instead of example compound 50b), the title compound was prepared in form of a solid (0.008 g, 4%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 9.79 (s a, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.7 (m, J = 7.7 Hz, 5H), 7.2 (m, 3H), 4.4 (m, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.47 (t, J = 7.0 Hz. 3H), MS (ES) m / z 497 (M + H) +.

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Example 52 3- {N '- [1- (3,4-dimethylphenyl) -3- (1-methylethoxy) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl

Following the procedure of example 50c), with the exception that example compound 44a) was used instead of example compound 50b), the title compound was prepared in form of a solid (0.008 g, 4%). MS (ES) m / z 511 (M + H) +.

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Example 53 3- {N '- [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino] -2-hydroxy-3'-tetrazol-5-ylbiphenyl to) 2- (4-Fluorophenyl) -5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that 4-fluorophenylhydrazine was used instead of 3,4-dimethylphenyl hydrazine, the title compound was prepared as a solid (3.0 g, 64%). MS (ES) m / z
192 (M + H) +.

b) 3- {N '- [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol  instead of acid 4-amino-3'-hydroxybiphenyl-3-carboxylic acid; hydrochloride salt and the compound of example 53a) instead of example compound 1d), the title compound was prepared (0.16 g, 60%). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.2 (s, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.95 (dd, J = 2.1 Hz, 9.2 Hz, 2H), 7.75 (m, 3H), 7.2 (m, 4H), 2.34 (s, 3H). MS m / z 457 (M + H) +.

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Example 54 3- {N '- [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5 -ylbiphenyl

Following the procedure of example 47b), with the exception that it was used 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol  instead of acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, the title compound was prepared as a solid (0.1 g, 37%) 1 H NMR (300 MHz, d 6 -DMSO) δ 13.7 (s at, 1H), 9.9 (s at, 1H), 8.2 (s, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.8 (m, 5H), 7.25 (m, 3H), 2.35 (s, 3H), 2.30 (s, 3H). MS m / z 471 (M + H) +.

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Example 55 3- {N '- [3-methyl-5-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 54), with the exception that the compound of 35a) was used instead of compound of 47a), the title compound was prepared in the form of a solid (0.115 g, 41%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 9.9 (br s, 1H), 8.25 (s, 1H), 8.17 (d, J = 8.6 Hz, 2H), 8.08 (s, J = 6.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.76 (m, 3H), 7.25 (m, 2H), 2.38 (s, 3H). MS (ES) m / z 505 (M + H) +.

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Example 56 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic to) 2- (3,4-Dimethylphenyl) -5-pyridin-4-yl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that ethyl benzylacetoacetate was used instead of ethyl acetoacetate, the title compound was prepared as of a solid (1.0 g, 29%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 11.9 (s a, 1H), 8.5 (d, J = 4.6 Hz, 2H), 7.78 (d, J = 4.6 Hz, 2H), 7.58 (s, 1H), 7.50 (dd, J = 2.1 Hz, 8.1 Hz, 1H), 7.2 (d, J = 8.1 Hz, 1H), 6.1 (s, 1H), 2.29 (s, 3H), 2.26 (s, 3H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic

Following the procedure of example 1e), with the exception that example compound 60a) was used instead of example compound 1d) and acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of acid 4-amino-3'-hydrobiphenyl-3-carboxylic acid,  the title compound was prepared (0.13 g, 68%). 1 H NMR (300 MHz, d 6 -DMSO) δ 14.4 (s at, 1H), 8.9 (s, 2H), 8.5 (s, 2H), 8.19 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.8 (m, 2H), 7.75 (d, J = 7.3 Hz, 1H), 7.65 (t, J = 8.7 Hz, 1H), 7.25 (m, 3H), 2.29 (s, 3H), 2.26 (s, 3H). MS (ES) m / z 506 (M + H) +.

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Example 57 3- {N '- [1- (3,4-Dimethylphenylpyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 56, with the exception that it was used 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol  instead of acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, the title compound was prepared as a solid (0.13 g, 61%). 1 H NMR (300 MHz, d 6 -DMSO) δ 14.4 (s at, 1H), 10.1 (s at, 1H), 8.9 (s, 2H), 8.65 (s, 2H), 8.3 (s, 1H), 8.13 (d, J = 7.4 Hz, 1H), 7.8 (m, 6H), 7.32 (m, 3H), 2.28 (s, 3H), 2.23 (s, 3H). MS (ES) m / z 530 (M + H) +.

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Example 58 3- {N '- [1- (3,4-dimethylphenyl) -3-pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino] -2-hydroxy-3'-tetrazol -5-ilbiphenyl to) 2- (3,4-dimethylphenyl) -5-pyridin-2-yl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that ethyl picolinyl acetate was used instead of ethyl acetoacetate, the title compound was prepared as of a solid (1.5 g, 44%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 11.7 (s, 1H), 8.59 (d, J = 4.7 Hz, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 4.9 Hz, 1H), 7.2 (d, J = 8.2 Hz, 1H), 6.05 (s, 1H), 2.29 (s, 3H), 2.26 (s, 3H).

b) 3- {N '- [1- (3,4-dimethylphenyl) -3-pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl

Following the procedure of example 1e), with the exception that example compound 58a) was used instead of compound of example 1d) and was used 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of acid 4-amino-3'-hydrobiphenyl-3-carboxylic acid, the title compound was prepared (0.17 g, 68%). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.9 (s at, 1H), 8.43 (br s, 1H), 8.29 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.80 (m, 5H), 7.65 (m, 1H), 7.23 (m, 3H), 2.29 (s, 3H), 2.26 (s, 3H). MS (ES) m / z 530 (M + H) +.

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Example 59 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-carboxylic

Following the procedure of example 58b), with the exception that acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic  instead of 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol, the title compound was prepared as a solid (0.08 g, 83%) 1 H NMR (300 MHz, d 6 -DMSO) δ 9.8 (s at, 1H), 8.9 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.19 (s, 2H), 7.98 (d, J = 8.1 Hz, 1H), 7.80 (m, 4H), 7.75 (t, J = 7.0 Hz, 2H), 7.1 (m, 3H), 2.29 (s, 3H), 2.26 (s, 3H). MS (ES) m / z 506 (M + H) +.

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Example 60 3- {N '- [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5 -ylbiphenyl to) 3-Fluoro-4-methylphenylhydrazine

It combined 3-fluoro-4-methylaniline (5.0 g, 40 mmol) with a mixture of acetic acid (125 ml), water (50 ml) and concentrated hydrochloric acid (50 ml).

The resulting solution was cooled in a bath of ice and treated portionwise with NaNO2 (3.1 g, 45 mmol) in water (50 ml). After the reaction mixture was stirred at low temperature for 15 minutes, was added to a chloride solution tin (45 g, 200 mmol) in 100 ml of hydrochloric acid concentrated; It also cooled in an ice bath. Then the reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The resulting suspension was extracted with ethyl acetate (400 ml) and the organic phase was washed with brine and dried over magnesium sulfate. Then, the solution was filtered and The solvent was removed under reduced pressure. Solid color yellow obtained in this way was partitioned between sodium hydroxide 1 M (200 ml) and ethyl acetate (600 ml) and the two-phase mixture is filtered and separated. The organic phase was washed with brine, dried over magnesium sulfate, it was filtered and the solvent was removed at reduced pressure The residue was taken up in diethyl ether and was He treated with hydrogen chloride gas. The resulting suspension is filtered and the precipitate was dried under vacuum to give the hydrochloride salt of the desired product in the form of a white solid (3.25 g, fifty%). 1 H NMR (300 MHz, d 6 -DMSO) δ 10.3 (s a, 1H), 8.4 (s a, 1H), 7.17 (t, J = 8.6 Hz, 1H), 6.83 (dd, J = 2.2 Hz, 8.2 Hz, 2H), 2.14 (s, 3H).

b) 2- (3-Fluoro-4-methylphenyl) -5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that the compound of 60a) was used instead of 3,4-dimethylphenylhydrazine, the compound was prepared of the title in the form of a solid (1.6 g, 76%). 1 H NMR (300 MHz, d 6 -DMSO) δ 11.6 (s at, 1H), 7.5 (m, 2H), 7.3 (t, J = 8.8 Hz, 1H), 5.3 (s, 1H), 2.23 (s, 3H), 2.1 (s, 3H). MS (ES) m / z 207 (M + H) +.

C) 3- {N '- [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5 -ylbiphenyl

Following the procedure of example 1e), with the exception that example compound 64b) was used instead of example compound 1d) and acid was used 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol during 4-amino-3'-hydrobiphenyl-3-carboxylic acid,  the title compound was prepared (0.07 g, 44%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s at, 1H), 9.9 (s a, 1H), 8.26 (s, 1H), 8.09 (d, J = 7.4 Hz, 1H), 7.7 (m, 5H), 7.38 (t, J = 8.3 Hz, 1H), 7.23 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H). EM (ES) m / z 471 (M + H) +.

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Example 61 Acid 3 '- {N' - [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 60c), with the exception that acid was used 3'-amino-2'-hydrobiphenyl-3-carboxylic  instead of 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol, the title compound was prepared as a solid (0.09 g, 33%) 1 H NMR (300 MHz, d 6 -DMSO) δ 13.7 (s a, 1H), 13.1 (s a, 1H), 9.9 (s a, 1H), 8.13 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.8 (d, J = 7.8 Hz, 1H), 7.72 (m, 3H), 7.38 (t, J = 8.3 Hz, 1H), 7.18 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H). EM (ES) m / z 447 (M + H) +.

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Example 62 Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylpyrimidin-2-yl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 3-methyl-1- (4-trifluoromethyl-2-pyrimidyl) -3-pyrazolin-5-one

3-Oxobutanoate was added ethyl (0.745 g, 5.73 mmol) to a stirred mixture of 2-hydrazino-4-trifluoromethylpyrimidine  (1.02 g, 5.73 mmol), sodium acetate (0.47 g, 5.73 mmol) and acid acetic (15 ml) and then the mixture was heated at reflux for 18 h. After a period of cooling, the acetic acid is removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase was washed with water and aqueous NaCl saturated, dried (MgSO 4) and evaporated under reduced pressure. He residue was chromatographed (silica gel, ethyl acetate) to give an impure product, which was partitioned between aqueous K2CO3 and ethyl acetate. The aqueous phase was washed with ethyl acetate, then acidified to pH 1 with aqueous HCl and extracted with acetate of ethyl. The extracts were dried (MgSO4) and evaporated to reduced pressure, giving the title compound (0.403 g; 29%) in form of a pale yellow solid. MS (ES) m / z 245 (M + H) +.

b) Acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethyl-2-pyrimidyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Ac. Sodium nitrite ac. Was added dropwise. 1 m (0.45 ml, 0.45 mmol) to a stirred acid solution 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid;  hydrochloride (0.100 g, 0.376 mmol) in aq. hydrochloric acid. 1 M (1 ml) / ethanol (5 ml) at 5 ° C. The mixture was stirred 10 min. at temperature atmosphere and added 3-methyl-1- (4-trifluoromethyl-2-pyrimidyl) -3-pyrazolin-5-one (0.092 g, 0.376 mmol), followed by sodium acid carbonate until the pH was 8. The reaction was stirred for 18 h and then partitioned between ac hydrochloric acid. and ethyl acetate. The Extracts were washed with Na 2 CO 3 aq. The aqueous phase is washed with ethyl acetate, then acidified to pH 1 with acid hydrochloric acid The solid was filtered, then purified by hplc preparative (ODS-silica, acetonitrile al 10-90% / water-0.1% TFA) for produce the title compound (0.035 g; 19%) in the form of a solid orange. MS (ES) m / z 485 (M + H) +.

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Example 63 3'-N- tert -butoxycarbonylamino-3- {N '- [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxybiphenyl a) 2'-Hydroxy-3'-nitrobiphenyl-3-yl-carbamic acid; tert -butyl ester

The compound of example 31b) (0.75 g, 3.3 mmol), 3'-amino-3-nitrobiphenyl-2-ol, in methylene chloride (10 ml) was treated with tert- butyl dicarbonate (0, 78 g, 3.6 mmol) at 0 ° C. The reaction mixture was heated to room temperature and stirred for 48 h. 10% sodium hydroxy was added, then stirred for 10 min and 3 N hydrochloride was added to neutralize the solution at pH = 7. The phases were separated and the organic phase was washed with water, dried over MgSO 4 and concentrated, giving a brown gum (0.77 g, 72%). 1 H NMR (300 MHz, d 6 -DMSO) δ 8.13 (d, J = 8.7 Hz, 1H), 7.65 (m, 2H), 7.3 (m, 3H), 7.08 (J = 8.7 Hz, 1H), 6.58 (sa, 1H), 1.32 (s, 6H), 1.28 (s, 3H).

b) 3'-N- tert -butoxycarbonylamino-3- {N '- [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2 -hydroxybiphenyl

Following the procedure of example 1c), with the exception that 2'-hydroxy-3'-nitrobiphenyl-3-yl-carbamic acid, tert- butyl ester was used instead of the compound of example 1b), the product was obtained in stupid. The above crude product (0.1 g, 0.33 mmol) in aq. Hydrochloric acid. 1 M (0.35 ml) was cooled to 5 ° C and then treated dropwise with a solution of sodium nitrite (0.035 g; 0.5 mmol) in water (5.0 ml). The yellow mixture was stirred at 5 ° C for an additional 10 min and then treated in one portion with the compound of Example 1d) (0.067 g, 0.3 mol) followed by portion addition of sodium acid carbonate and ethanol ensuring that The final pH of the reaction mixture was about 7-8. Then, the red solution was stirred at room temperature for 24 h. The mixture was filtered to give a red solid that was suspended in water and then acidified with concentrated hydrochloric acid. Filtration produced the title compound (0.12 g; 71%) as a red powder. MS (ES) m / z 514 (M + H) +.

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Example 64 3'-amino-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxybiphenyl

The compound of example 63b) (0.03 g, 0.06 mmol) was treated with 0.45 ml of trifluoroacetic acid in methylene (5 ml). After stirring at room temperature for 2 h, the reaction mixture was concentrated and washed with diethyl ether, giving the title compound as a red powder (0.02 g, 65%). MS (ES) m / z 414 (M + H) +.

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Example 65 3- {N '- [1- (3-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl to) 2- (3-fluorophenyl) -5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that hydrochloride was used 3-fluorophenylhydrazine instead of hydrochloride 3,4-dimethylphenylhydrazine, the compound was prepared of the title in the form of a solid (4.6 g, 73%). MS (ES) m / z 193 (M + H) +.

b) 3- {N '- [1- (3-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 2- (3-fluorophenyl) -5-methyl-2,4-dihydropyrazol-3-one  instead of the 1d compound) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of compound 1c), the title compound was obtained in form of a solid (0.03 g, 18%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 8.2 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.8 (m, 5H), 7.53 (m, 1H), 7.21 (m, 2H), 7.08 (t, J = 7.8 Hz, 1H), 2.37 (s, 3H). MS (ES) m / z 457 (M + H) +.

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Example 66 Acid 3 '- {N' - [1- (3-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-2'-hydroxybiphenyl-3-carboxylic  instead of acid 4'-amino-2'-hydroxybiphenyl-3-carboxylic Y 2- (3-fluorophenyl) -5-methyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d), the compound of the title in the form of a solid (0.07 g, 45%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 9.7 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.8 (m, 4H), 7.64 (t, J = 7.7 Hz, 1H), 7.52 (m, 1H), 7.2 (m, 2H), 7.07 (t, J = 7.2, 1H), 2.35 (s, 3H). MS (ES) m / z 433 (M + H) +.

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Example 67 3 {N '- [3-methyl-5-oxo-1- (2,3,4,5,6-pentafluorophenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} 1-2-hydroxy-3' -tetrazol-5-ylbiphenyl to) Methyl-pentafluorophenyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that pentafluorophenylhydrazine hydrochloride was used instead of 3,4-dimethylphenylhydrazine hydrochloride, the title compound was prepared as a solid (1.7 g, 25%) MS (ES) m / z 265 (M + H) +.

b) 3- {N '- [3-methyl-5-oxo-1- (2,3,4,5,6-pentafluorophenyl), 1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3' -tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that methyl was used pentafluorophenyl-2,4-dihydropyrazol-3-one  instead of the compound of 1 d) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of compound 1c), the title compound was obtained in form of a solid (0.04 g, 23%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 9.9 (s, 1H), 8.2 (s, 1H), 8.07 (d, J = 7.3 Hz, 1H), 7.76 (m, 3H), 7.23 (m, 2H), 2.34 (s, 3H). MS (ES) m / z 529 (M + H) +.

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Example 68 Acid 3 '- {N' - [3-methyl-5-oxo-1- (2,3,4,5,6-pentafluorophenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-carboxylic

Following the procedure of example 1e), with the exception that methyl was used pentafluorophenyl-2,4-dihydropyrazol-3-one  instead of the compound of 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of compound 1c), the title compound was obtained in form of a solid (0.1 g, 51%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 9.8 (s, 1H), 8.12 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.2 (m, 2H), 2.34 (s, 3H). EM (ES) m / z 505 (M + H) +.

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Example 69 Acid 3 '- {N' - [1- (3,4-Difluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (3,4-Difluorophenyl-5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that hydrochloride was used 3,4-difluorophenylhydrazine instead of hydrochloride 3,4-dimethylphenylhydrazine, the compound was prepared of the title in the form of a solid (0.82 g, 70%). MS (ES) m / z 211 (M + H) +.

b) Acid 3 '- {N' - [1- (3,4-Difluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,4-Difluorophenyl-5-methyl-2,4-dihydropyrazol-3-one  instead of the compound of 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of compound 1c), the title compound was obtained in form of a solid (0.11 g, 57%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.6 (s a, 1H), 13.1 (s a, 1H), 9.9 (s at, 1H), 8.1 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.94 (dd, J = 7.5 Hz, 2.4 Hz, 1H), 7.76 (m, 3H), 7.62 (t, J = 7.8 Hz, 1H), 7.55 (m, 1H), 7.19 (m, 2H), 2.34 (s, 3H). MS (ES) m / z 451 (M + H) +.

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Example 70 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (3,4-dimethylphenyl) -5-methoxymethyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that 4-methoxyacetoacetate was used methyl instead of ethyl acetoacetate, the compound of the title in the form of a solid (2.7 g, 58%). MS (ES) m / z 233 (M + H) +.

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-methoxymethyl-2,4-dihydropyrazol-3-one  instead of the compound of 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of compound 1c), the title compound was obtained in form of a solid (0.189 g, 64%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.9 (s a, 1H), 13.1 (s a, 1H), 9.9 (s at, 1H), 8.1 (s, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 6.5 Hz, 1H), 7.71 (s, 1H), 7.65 (m, 3H), 7.2 (m, 3H), 4.5 (s, 2H), 3.4 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H). MS (ES) m / z 473 (M + H) +.

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Example 71 3- {N '- [1- (3,4-dimethylphenyl) -3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-methoxymethyl-2,4-dihydropyrazol-3-one  instead of the 1d compound) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of compound 1c), the title compound was obtained in form of a solid (0.126 g, 67%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.9 (s at, 1H), 9.9 (s, 1H), 8.25 (s, 1H), 8.09 (d, J = 7.4 Hz, 1H), 7.78 (m, 3H), 7.71 (s, 1H), 7.65 (dd, J = 2.1 Hz and 7.2 Hz, 1H), 7.25 (m, 3H), 4.5 (s, 2H), 3.4 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H). MS (ES) m / z 497 (M + H) +.

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Example 72 3- {N '- [1- (3,4-Difluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 2- (3,4-Difluorophenyl-5-methyl-2,4-dihydropyrazol-3-one  instead of the 1d compound) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of compound 1c), the title compound was obtained in form of a solid (0.095 g, 56%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.25 (s, 1H), 8, 1 (d, J = 7.3 Hz, 1H), 7.95 (m, 1H), 7.78 (m, 4H), 7.58 (m, 1H), 7.22 (m, 2H), 2.37 (s, 3 H). MS (ES) m / z 475 (M + H) +.

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Example 73 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-trifluoromethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 3,4-dimethylphenyltrifluoromethyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 4,4,4-trifluoro-3-oxo-butyric  instead of 3,4-dimethylphenylhydrazine hydrochloride, the title compound was prepared as a solid (4.0 g, 52%) MS (ES) m / z 257 (M + H) +.

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-trifluoromethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 3,4-dimethylphenyltrifluoromethyl-2,4-dihydropyrazol-3-one  instead of the compound of 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of compound 1c), the title compound was obtained in form of a solid (0.012 g, 4%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.1 (s a, 1H), 10.1 (s at, 1H), 8.1 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.6 (m, 3H), 7.27 (m, 2H), 7.55 (m, 1H), 7.2 (t, J = 7.8 Hz, 1H), 2.30 (s, 3H), 2.26 (s, 3H). MS (ES) m / z 497 (M + H) +

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Example 74 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -6-fluoro-2'-hydroxybiphenyl-3- carboxylic a) Acid 5'-Chloro-6-fluoro-2'-methoxybiphenyl-3-carboxylic acid

Following the procedure of example 1 b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid and acid 3-Bromo-4-fluorobenzoic acid, the title compound was prepared as a solid (0.2 g, 16%) MS (ES) m / z 281 (M + H) +, 561 (2M + H) +.

b) Acid 5'-Chloro-6-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure in example 3d), with the exception that acid was used 5'-Chloro-6-fluoro-2'-methoxybiphenyl-3-carboxylic acid  instead of the compound of example 3c), the compound of the title in the form of a solid (1.1 g, 59%). MS (ES) m / z 267 (M + H) +.

c) Acid 5'-Chloro-6-fluoro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid

Following the procedure of example 7c), with the exception that acid was used 5'-Chloro-6-fluoro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid  instead of acid 6- (5-Chloro-2-hydroxyphenyl) -pyridine-2-carboxylic acid, the title compound was prepared as a solid (1 g, 86%) MS (ES) m / z 312 (M + H) +, 623 (2M + H) +. 1 H NMR (300 MHz, d_ {6} -DMSO) δ 10.8 (s, 1 H), 8.13 (d, J = 2.7 Hz, 1H), 8.09 (m, 1H), 8.0 (dd, J = 7.1 Hz, 2.2 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.48 (t, J = 9.0, 1H).

d) Acid 5'-Chloro-6-fluoro-2'-hydroxy-3'-aminobiphenyl-3-carboxylic acid

Following the procedure of Example 1c), with the exception that acid was used 5'-Chloro-6-fluoro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid  instead of the compound of 1b), the crude product was isolated. MS m / z 248 (M + H) +.

e) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -6-fluoro-2'-hydroxybiphenyl-3- carboxylic

Following the procedure of example 1e), with the exception that acid was used 5'-Chloro-6-fluoro-2'-hydroxy-3'-aminobiphenyl-3-carboxylic acid  instead of the compound of example 1c), the compound of the title in the form of a solid (0.25 g, 42%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 13.1 (s a, 1H), 9.8 (s, 1H), 8.08 (m, 2H), 7.78 (dd, J = 7.0 Hz, 2.8 Hz, 1H), 7.71 (s, 1H), 7.65 (dd, J = 2, 1 Hz, 8.1 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.14 (m, 2H), 2.34 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). MS (ES) m / z 461 (M + H) +.

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Example 75 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (3,4-dimethylphenyl) -5-propyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that ethyl butyrylacetate was used instead of ethyl acetoacetate, the title compound was prepared as of a solid (3.0 g, 64%). 1 H NMR (300 MHz, CDCl 3) δ 7.61 (s, 1H), 7.56 (dd, J = 2.3 Hz and 8.2 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 3.39 (s, 2H), 2.47 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.64 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-propyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.145 g, 93%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 9.7 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.8 (d, J = 7.8 Hz, 1H), 7.62 (m, 4H), 7.62 (m, 3H), 2.7 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.8 (m, 2H), 1.1 (t, J = 7.4 Hz, 3H).

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Example 76 3- {N '- [1- (3,4-dimethylphenyl) -5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-propyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of the compound of example 1c), the compound of the title in the form of a solid (0.06 g, 36%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.27 (s, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.78 (m, 3H), 7.65 (d, J = 8.2 Hz, 1H), 7.18 (m, 4H), 2.7 (t, J = 7.5 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.8 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). MS (ES) m / z 495 (M + H) +.

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Example 77 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methyl-1 H -pyrrole-3-yl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl-3-carboxylic a) Acid 3- (1-methyl-1H-pyrrole-3-yl) -3-oxo-propionic, ethyl ester

At a suspension of 60% sodium hydride (5.1 g, 128 mmol) and diethyl carbonate (10.3 ml, 85 mmol) in benzene are he added dropwise a solution of 3-acetyl-1-methylpyrrole (5.25 g, 43 mmol) in benzene for 45 min. Then the mixture is heated for 30 min and the mixture thickened to a paste at the end of the reaction. The mixture was cooled, diluted with acetate. of ethyl and carefully acidified with acetic acid. Was added water, the phases were separated and the aqueous phase was extracted with acetate of ethyl (2 times). The combined organic extracts were washed with water, dried and concentrated under reduced pressure, giving the raw product. The crude product was further purified by column chromatography on SiO2 (ethyl acetate at 50% / hexane), giving the title compound (7.4 g, 89%). 1 H NMR (300 MHz, CDCl 3) δ 7.26 (s, 1H), 6.5 (s, 2H), 4.1 (m, 2H), 3.68 (s, 2H), 3.64 (s, 3H), 1.2 (t, 7.2 Hz, 3H).

b) 2- (3,4-dimethylphenyl) -5- (1-methyl-1H-pyrrole-3-yl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 3- (1-methyl-1H-pyrrole-3-yl) -3-oxo-propionic,  ethyl ester instead of ethyl acetoacetate, the title compound as a solid (3.0 g, 62%). MS m / z 268 (M + H) +.

c) 3 '- {N' - [1- (3,4-Dimethylphenyl) -3- (1-methyl-1 H -pyrrol-3-yl) -5-oxo-1,5-dihydropyrazole-4- acid ilidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-propyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.099 g, 43%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 14.0 (s a, 1H), 9.6 (s, 1H), 8.15 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.82 (m, 3H), 7.72 (dd, J = 2.1 Hz and 8.1 Hz, 1H), 7.63 (m, 2H), 7.23 (m, 3H), 6.89 (t, J = 2.5 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 3.89 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H). MS (ES) m / z 508 (M + H) +.

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Example 78 3- {N '- [1- (3,4-dimethylphenyl) -3- (1-methyl-1H-pyrrol-3-yl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} - 2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5- (1-methyl-1H-pyrrole-3-yl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of the compound of example 1c), the compound of the title in the form of a solid (0.078 g, 35%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 14.0 (s a, 1H), 9.7 (s, 1H), 8.26 (s, 1H), 8.1 (d, J = 7.5 Hz, H), 7.85 (t, J = 5.0 Hz, 1H), 7.82 (s, 1H), 7.75 (m, 3H), 7.62 (s, 1H), 7.24 (s, 3H), 6.9 (s, 1H), 6.7 (s, 1H), 3.89 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H). MS (ES) m / z 532 (M + H) +.

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Example 79 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic to) 2- (3,4-dimethylphenyl) -5-furan-2-yl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that it was used -oxo-3-ethyl furanpropionate in instead of ethyl acetoacetate, the title compound was prepared in form of a solid (2.0 g, 48%). 1 H NMR (300 MHz, CDCl 3) δ 7.74 (s, 1H), 7.7 (s, 1H), 7.6 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.2 (d, J = 7.8 Hz, 1H), 6.8 (s, 1H), 3.68 (s, 2H), 2.3 (s, 3H), 2.2 (s, 1H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic

Following the procedure of example 1e), with the exception that 2- (3,4-dimethylphenyl) -5-furan-2-yl-2,4-dihydropyrazol-3-one was used instead of the compound of example 1d) and 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid instead of the compound of example 1c), the title compound was obtained as a solid (0.22 g, 11%). 1 H NMR (300 MHz, d 6 -DMSO) δ 14.0 (s, 1 H), 9.8 (s, 1 H), 8.55 (s, 1 H), 8.15 ( s, 1H), 7.95 (m, 2H), 7.82 (m, 2H), 7.71 (dd, J = 2.0 Hz
and 8.0 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.23 (m, 3H), 7.1 (s, 1H), 2.3 (s, 3H ), 2.2 (s, 3H). MS (ES) m / z 495 (M + H) +.

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Example 80 3- {N '- [1- (3,4-dimethylphenyl) -3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-furan-2-yl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of the compound of example 1c), the compound of the title in the form of a solid (0.022 g, 11%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 14.0 (s, 1H), 9.8 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.1 (d, J = 7.5 Hz, 1H), 7.96 (dd, J = 2.0 Hz and 7.7 Hz, 1H), 7.9 (s, 1H), 7.75 (m, 4H), 7.25 (m, 3H), 7.1 (s, 1H), 2.3 (s, 3H), 2.2 (s, 3H). MS (ES) m / z 495 (M + H) +.

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Example 81 N- (2'-hydroxy-3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethyl-phenyl) -1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl- 3-yl) -1,1,1-trifluoromethanesulfonamide to) 1,1,1-trifluoro-N- (2'-hydroxy-3'-aminobiphenyl-3-yl) -methanesulfonamide

Following the procedure of example 1c) with the exception that it was used 1,1,1-trifluoro-N- (2'-hydroxy-3'-nitrobiphenyl-3-yl) -methanesulfonamide  instead of the compound of example 1b), the compound of the title (100%). H NMR (300 MHz, CDCl 3) δ 7.4 (m, 3H), 7.17 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 7.8 Hz, 2H), 6.55 (t, J = 7.5 Hz, 1H).

b) N- (2'-hydroxy-3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethyl-phenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} biphenyl-3- il) -1,1,1-trifluoromethanesulfonamide

Following the procedure of example 1e), with the exception that it was used 5-methyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 1,1,1-trifluoro-N- (2'-hydroxy-3'-aminobiphenyl-3-yl) -methanesulfonamide  instead of the compound of example 1c), the compound of the title in the form of a solid (0.041 g, 18%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s, 1H), 9.8 (s, 1H), 8.19 (d, J = 8.6 Hz, 2H), 7.8 (d, J = 9.0 Hz, 2H), 7.7 (d, J = 2.8 Hz and 6.9 Hz, 1H), 7.5 (m, 3H), 7.3 (d, J = 6.0 Hz, 1H), 7.15 (m, 2H), 2.35 (s, 3H). MS (ES) m / z 586 (M + H) +.

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Example 82 N - (2'-hydroxy-3 '- { N ' - [1- (3-fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl-3-yl) -1,1,1-trifluoromethanesulfonamide

Following the procedure of example 1e), with the exception that it was used 5-methyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 2- (3-Fluoro-4-methylphenyl) -5-methyl-2,4-dihydropyrazol-3-one instead of the compound of example 1c), the compound of the title in the form of a solid (0.038 g, 17%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s, 1H), 9.8 (s, 1H), 7.7 (m, 3H), 7.54 (t, J = 7.8 Hz, 1H), 7.5 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 8.3 Hz, 1H), 7.3 (d, J = 6.0 Hz, 1H), 7.15 (m, 2H), 2.35 (s, 3H), 2.3 (s, 3H). MS (ES) m / z 550 (M + H) +.

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Example 83 N- (2'-hydroxy-3 '- {N' - [1- (4-fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl-3-yl) -1,1,1-trifluoromethanesulfonamide

Following the procedure of example 1e), with the exception that it was used 5-methyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 2- (4-Fluoro-3-methylphenyl) -5-methyl-2,4-dihydropyrazol-3-one instead of the compound of example 1c), the compound of the title in the form of a solid (0.042 g, 18%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s. 1H), 9.8 (s, 1H), 7.83 (dd, J = 1.8 Hz and 7.5 Hz, 1H), 7.75 (m, 1H), 7.73 (dd, J = 2.0 and 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.45 (m, 2H), 7.2 (m, 5H), 2.35 (s, 3H), 2.3 (s, 3H). MS (ES) m / z 550 (M + H) +.

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Example 84 N - (2'-hydroxy-3 '- { N' - [1- (3,4-difluorophenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl- 3-yl) -1,1,1-trifluoromethanesulfonamide

Following the procedure of example 1e), with the exception that it was used 5-methyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 2- (3,4-Difluorophenyl) -5-methyl-2,4-dihydropyrazol-3-one instead of the compound of example 1c), the compound of the title in the form of a solid (0.045 g, 20%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s, 1H), 9.8 (s. 1H). 7.98 (m, 1H), 7.78 (m, 1H), 7.73 (dd, J = 2.7 and 7.0 Hz, 1H), 7.53 (m, 4H), 7.3 (d, J = 5.6 Hz, 1H), 7.18 (m, 2H), 2.35 (s, 3H). MS (ES) m / z 554 (M + H) +.

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Example 85 N - (3 '- { N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-yl ) guanidine

It was treated 3'-amino-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxybiphenyl  (0.065 g, 0.16 mmol) in methylene chloride (10 ml) with 1,3-di-Boc-2-methyl isothiourea (0.055 g, 0.19 mmol). The reaction mixture was stirred at room temperature for 18 h. Then, 1.5 ml of trifluoroacetic acid in 20 ml of methylene chloride and the mixture The reaction was stirred for a further 18 h. After the concentration, The resulting gum was washed with diethyl ether, giving the compound. of the title in the form of a red powder (0.03 g, 58%). EM (ES) m / z 456 (M + H) +.

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Example 86 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (3,4-dimethylphenyl) -5-ethyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that ethyl propionyl acetate was used instead of ethyl acetoacetate, the title compound was prepared as of a solid (3.4 g, 46%). 1 H NMR (300 MHz, CDCl 3) δ 7.6 (s, 1H), 7.56 (dd, J = 2.2 Hz and 8.4 Hz, 1H), 7.1 (d, J = 8.4 Hz, 1H), 3.4 (s, 2H), 2.5 (m, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.2 (t, J = 7.5 Hz, 3H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-ethyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.035 g, 19%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.8 (s, 1H), 9.7 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.65 (m, 5H), 7.1 (m, 3H), 2.5 (m, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.3 (t, J = 7.5 Hz, 3H). MS (ES) m / z 457 (M + H) +.

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Example 87 3- {N '- [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-ethyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and 5- (2'-hydroxybiphenyl-3'-amino-3-yl) -1H-tetrazol instead of the compound of example 1c), the compound of the title in the form of a solid (0.055 g, 29%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.8 (s, 1H), 9.8 (s, 1H), 8.25 (s, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.76 (m, 4H), 7.65 (d, J = 7.2 Hz, 1H), 7.22 (m, 3H), 2.5 (m, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.3 (t, J = 7.5 Hz, 3H).

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Example 88 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thien-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic a) Acid 3-oxo-3-thiophene-2-yl-propionic, ethyl ester

Following the procedure of example 77a), with the exception that 2-acetyl thiophene was used instead from 3-acetyl-1-methylpyrrole,  the title compound was prepared in the form of an oil (7 g, 64%) 1 H NMR (300 MHz, CDCl 3) δ 7.75 (d, J = 3.8 Hz, 1H), 7.69 (d, J = 4.9 Hz, 1H), 7.1 (t, J = 4.9 Hz, 1H), 4.2 (m, 2H), 3.9 (s, 2H), 1.2 (t, J = 7.2 Hz, 3H).

b) 2- (3,4-dimethylphenyl-5-thiophene-2-yl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 3-oxo-3-thiophene-2-yl-propionic,  ethyl ester instead of ethyl acetoacetate, the title compound as a solid (3.4 g, 48%). 1 H NMR (300 MHz, CDCl 3) δ 7.52 (s, 1H), 7.46 (m, 3H), 7.2 (d, J = 8.1 Hz, 1H), 7.1 (t, J = 3.8 Hz, 1H), 5.9 (s. 1H), 2.28 (s, 3H), 2.25 (s, 3H).

c) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thien-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic

Following the procedure of example 1e), with the exception that it was used 2- (3,4-Dimethylphenyl-5-thiophene-2-yl-2,4-dihydro-pyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.09 g, 44%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 14.0 (s, 1H), 9.8 (s, 1H), 8.14 (s, 1H), 8.01 (d, J = 3.7 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.82 (m, 4H), 7.65 (m, 2H), 7.25 (m, 4H), 2.29 (s, 3H), 2.24 (s, 3H). MS (ES) m / z 511 (M + H) +.

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Example 89 Acid 3 '- {N' - [3-cyclopropyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid a) Acid 3-cyclopropyl-3-oxo-propionic, ethyl ester

Following the procedure of example 77a), with the exception that cyclopropylmethyl ketone was used instead of 3-acetyl-1-methylpyrrole, the title compound was prepared as a solid (5.5 g, 90%) 1 H NMR (300 MHz, CDCl 3) δ 4.2 (m, 2H), 3.55 (s, 2H), 2.1 (m, 1H), 1.3 (t, J = 7.2 Hz, 3H), 1.2 (m, 2H), 1.0 (m, 2H).

b) 2- (3,4-dimethylphenyl-5-thiophene-2-yl-2,4-dihydropyrazol-3-one

Following the procedure of example 1 d), with the exception that acid was used 3-cyclopropyl-3-oxo-propionic,  ethyl ester instead of ethyl acetoacetate, the title compound as a solid (3.9 g, 64%). MS m / z 229 (M + H) +.

c) Acid 3 '- {N' - [3-cyclopropyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,4-Dimethylphenyl-5-thiophene-2-yl-2,4-dihydro-pyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.07 g, 29%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.8 (s, 1H), 9.7 (s, 1H), 8.14 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.8 (d, J = 7.9 Hz, 1H), 7.7 (m, 4H), 7.01 (m, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 2.16 (m, 1H), 1.19 (m, 2H), 1.18 (m, 2H). MS (ES) m / z 469 (M + H) +.

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Example 90 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiazol-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic a) Acid 3-oxo-3-thiazol-2-yl-propionic, ethyl ester

Following the procedure of example 77a), with the exception that 2-acetylthiazone was used instead of 3-acetyl-1-methylpyrrole,  the title compound was prepared as a solid (1.7 g, twenty-one%). MS (ES) m / z 200 (M + H) +.

b) 2-methyl-5-thiazol-2-yl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 3-oxo-3-thiazol-2-yl-propionic,  ethyl ester instead of ethyl acetoacetate, the title compound as a solid (0.35 g, 15%). MS m / z 272 (M + H) +.

c) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiazol-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic

Following the procedure of example 1e), with the exception that it was used 2-methyl-5-thiazol-2-yl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (60 mg, 32%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.0 (s a, 1H), 9.7 (s, 1H), 8.16 (s, 1H), 7.99 (m, 2H), 7.7 (m, 5H), 7.2 (m, 3H), 2.27 (s, 3H), 2.23 (s, 3 H). MS (ES) m / z 512 (M + H) +.

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Example 91 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid a) Acid 1- (3,4-dimethylphenyl) -5-oxo-4,5-dihydro-1H-pyrazol-4-carboxylic acid, ethyl ester

Following the procedure of example 1d), with the exception that diethyl (ethoxymethylene) malonate was used  instead of ethyl acetoacetate, the title compound was prepared in the form of a solid (2.68 g, 89%). 1 H NMR (300 MHz, CDCl 3) δ 7.7 (s, 1H), 7.55 (s, 1H), 7.5 (d, J = 7.8 Hz, 1H), 7.2 (d, J = 7.8 Hz, 1H), 4.3 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 1.4 (t, J = 7.5 Hz, 3H). MS (ES) m / z 261 (M + H) +.

b) 2- (3,4-dimethylphenyl) -2,4-dihydropyrazol-3-one

The compound of example 91 c) (1.34 g, 5.15 mmol) in 10 ml of methanol was treated with a 10% solution of sodium hydroxy. After stirring at room temperature for three hours, the reaction mixture was heated to 100 ° C and stirred at this temperature for 48 h. 3N hydrochloride was added to acidify the mixture at pH = 4. Ethyl acetate was added and the phases were separated. The organic phases were combined, dried over MgSO4 and concentrated, giving the title compound as of a yellow powder (1.5 g, 87%). 1 H NMR (300 MHz, CDCl 3) δ 7.6 (s, 1H), 7.4 (dd, J = 2.4 Hz and 8.2 Hz, 1H), 7.47 (s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 3.5 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H). MS (ES) m / z 377 (2M + H) +.

c) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.927 g, 88%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 8.19 (s, 1H), 8.1 (s, 1H), 7.9 (d, J = 7.5 Hz, 1H), 7.8 (d, J = 7.5 Hz, 1H), 7.65 (m, 3H), 7.2 (m, 3H), 2.27 (s, 3H), 2.23 (s, 3H). MS (ES) m / z 429 (M + H) +.

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Example 92 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic to) 2- (3,4-dimethylphenyl) -5-isopropyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that isobutyryl ethyl acetate was used instead of ethyl acetoacetate, the title compound was prepared as of a solid (3.8 g, 66%). 1 H NMR (300 MHz, CDCl 3) δ 7.67 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 3.5 (s, 2H), 2.75 (m, 1H), 2.28 (s, 3H), 2.25 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino) -2'-hydroxybiphenyl-3- carboxylic

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-isopropyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.15 g, 71%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.8 (s, 1H), 9.6 (s, 1H), 8.14 (s, 1H), 8.1 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.65 (m, 2H), 7.10 (m, 3H), 3.17 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H). MS (ES) m / z 471 (M + H) +.

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Example 93 Acid 3 '- {N' - [3- (benzyloxymethyl) -1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid a) Acid 4-benzyloxy-3-oxo-butyric acid, ethyl ester

A suspension of sodium hydride (60% in oil) in toluene (200 ml) was mechanically stirred at temperature atmosphere under argon and treated dropwise with alcohol benzyl in toluene (40 ml) for 40 minutes. The mixture was stirred. for 1 hour, it was treated with ethyl 4-chloroacetate and then stirred for 18 hours at room temperature.

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At the end of the reaction, citric acid was added and the phases separated. The organic phases were washed with water, dried over MgSO4 and concentrated to give the title compound (7.2 g, 20%). MS (ES) m / z 237 (M + H) +.

b) 5-benzyloxymethyl-2- (3,4-dimethylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 4-benzyloxy-3-oxo-butyric acid,  ethyl ester instead of ethyl acetoacetate, the title compound as a solid (1.7 g, 37%). 1 H NMR (300 MHz, CDCl 3) δ 7.58 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.35 (m, 5H), 7.16 (d, J = 8.1 Hz, 1H), 4.6 (s, 2H), 4.37 (s, 2H), 3.5 (s, 2H), 2.29 (s, 3H), 2.25 (s, 3H).

c) Acid 3 '- {N' - [3- (benzyloxymethyl) -1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 5-benzyloxymethyl-2- (3,4-dimethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.023 g, 12%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.1 (s a, 1H), 9.8 (s a, 1H), 8.15 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.56 (m, 4H), 7.40 (m, 5H), 7.18 (m, 3H), 4.69 (s, 2H), 4.64 (s, 2H), 2.28 (s, 3H), 2.26 (s, 3H). MS (ES) m / z 549 (M + H) +.

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Example 94 Acid 3 '- {N' - [3-ethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 5-ethyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that propionyl ethyl acetate was used instead of ethyl acetoacetate and 4- (trifluoromethyl) phenyl hydrazine in instead of 3,4-dimethylphenylhydrazine hydrochloride, it prepared the title compound as a solid (9.6 g, 99%). 1 H NMR (300 MHz, CDCl 3) δ 8.07 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 3.45 (s, 2H), 2.55 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H).

b) Acid 3 '- {N' - [3-ethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 5-ethyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.1 g, 12%). 1 H NMR (300 MHz, d 6 -DMSO) 13.6 (s at, 1H), 13.1 (br s. 1H), 9.8 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.80 (m, 3H), 7.72 (d, J = 7.1 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.19 (m, 2H), 2.55 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H).

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Example 95 Acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic a) Acid 1- (4-Trifluoromethylphenyl) -5-oxo-4,5-dihydro-1H-pyrazol-4-carboxylic acid, ethyl ester

Following the procedure of example 1d), with the exception that diethyl (ethoxymethylene) malonate was used  instead of ethyl acetoacetate and trifluoromethylhydrazine instead of 3,4-dimethylphenylhydrazine, the compound was prepared of the title in the form of a solid. 1 H NMR (300 MHz, CDCl 3) δ 8.0 (d, J = 8.2 Hz, 2H), 7.64 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 4.18 (m, 2H), 1.25 (m, 3H). MS (ES) m / z 301 (M + H) +.

b) 2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 91b), with the exception that acid was used 1- (4-Trifluoromethylphenyl) -5-oxo-4,5-dihydro-1H-pyrazol-4-carboxylic acid,  ethyl ester instead of acid 1- (3,4-dimethylphenyl) -5-oxo-4,5-dihydro-1H-pyrazol-4-carboxylic acid, ethyl ester, the title compound was prepared as a solid. 1 H NMR (300 MHz, CDCl 3) δ 8.0 (d, J = 8.2 Hz, 2H), 7.7 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 3.56 (s, 2H). EM (ES) m / z 229 (M + H) +.

c) Acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic

Following the procedure of example 1e), with the exception that it was used 2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.25 g, 61%). MS (ES) m / z 469 (M + H) +.

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Example 96 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-hydroxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

It was treated 5-benzyloxymethyl-2- (3,4-dimethylphenyl) -2,4-dihydropyrazol-3-one (0.5 g, 0.002 mol) in THF with 10% Pd / C (cat.). The mixture of reaction was stirred for 4 hours under hydrogen atmosphere (344.74 kPa (50 psi)). At the end of the reaction, the mixture was concentrated and purified by column chromatography on SiO2, giving the raw product in the form of a gum (0.15 g, 34%).

Following the procedure of example 1e), with the exception that the previous raw product was used instead of compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.11 g, 65%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 9.7 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.7 (m, 5H), 7.19 (m, 3H), 2.28 (s, 3H), 2.26 (s, 3 H). MS (ES) m / z 459 (M + H) +.

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Example 97 Acid 3 '- {N' - [3-benzyloxymethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 5-benzyloxymethyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 4-benzyloxy-3-oxo-butyric acid,  ethyl ester instead of ethyl acetoacetate and 4-trifluoromethylphenylhydrazine instead of 3,4-dimethylhydrazine, the compound of the title in the form of a solid (1.6 g, 32%). 1 H NMR (300 MHz, DMSO-d_6) δ 8.0 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.35 (m, 5H), 5.6 (s, 1H), 4.53 (s, 2H), 4.41 (s, 2H). MS (ES) m / z 349 (M + H) +.

b) Acid 3 '- {N' - [3-benzyloxymethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 5-benzyloxymethyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.018 g, 8%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 9.8 (s, 1 H), 8.20 (d, J = 7.6 Hz, 2H), 8.14 (s, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 7.1 Hz, 1H), 7.63 (m, 2H), 7.38 (m, 5H), 7.21 (m, 2H), 4.71 (s, 2H), 4.68 (s, 2H). MS (ES) m / z 589 (M + H) +.

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Example 98 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methylsulfanylmethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid a) Acid 4-methylsulfanyl-3-oxo-butyric acid, ethyl ester

To a solution of sodium thiomethoxide (5.0 g, 0.071 mol) in methanol (100 ml), stirred at 5 ° C in a stream slow nitrogen, a solution of Ethyl 4-chloroacetoacetate (6.76 ml, 0.05 mol) in methanol The reaction mixture was heated to room temperature and stirred for 18 hours. At the end of the reaction, methanol is evaporated and the aqueous phase was extracted with ether (3 times). The Combined organic extracts were dried and concentrated. He residue was further purified by distillation to 70-80 ° C (0.1 mmHg), giving the title compound. MS (ES) m / z 163 (M + H) +, 177 (M + H) +. (mixture of methyl ester and ethyl ester).

b) 2- (3,4-dimethylphenyl) -5-methylsulfanylmethyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 4-methylsulfanyl-3-oxo-butyric acid,  ethyl ester instead of ethyl acetoacetate, the title compound as a solid (0.6 g, 16%). 1 H NMR (300 MHz, DMSO-d 6) δ 7.52 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.48 (s, 1H), 3.5 (s, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H).

c) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methylsulfanylmethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-methylsulfanylmethyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.09 g, 49%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s at, 1H), 9.8 (s, 1H), 8.15 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.74 (m, 2H), 7.65 (m, 2H), 7.19 (m, 3H), 3.79 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H). MS (ES) m / z 489 (M + H) +.

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Example 99 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic a) Acid 3-oxo-3-thiophene-3-yl-propionic, ethyl ester

Following the procedure of example 77a), with the exception that 3-acetylthiophene was used instead of 3-acetyl-1-methyl-pyrazole,  the title compound was prepared as a solid (9.8 g, 74%) 1 H NMR (300 MHz, DMSO-d 6) δ 8.08 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.30 (s, 1H), 4.19 (m, 2H), 3.86 (s, 2H), 1.28 (m, 3H).

b) 2- (3,4-dimethylphenyl) -5-thiophene-3-yl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 3-oxo-3-thiophene-3-yl-propionic,  ethyl ester instead of ethyl acetoacetate, the title compound as a solid (0.95 g, 27%). 1 H NMR (300 MHz, DMSO-d 6) δ 7.8 (s, 1H), 7.57 (m, 4H), 7.18 (d, J = 8.3 Hz, 1H), 5.89 (s, 1H), 2.27 (s, 3H), 2.24 (s, 3 H).

c) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic

Following the procedure of example 1e), with the exception that it was used 2- (3,4-dimethylphenyl) -5-thiophene-3-yl-2,4-dihydro-pyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.09 g, 46%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.9 (s a, 1H), 13.1 (s a, 1H), 9.8 (s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.16 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.67 (m, 5H), 7.19 (m, 3H), 2.27 (s, 3H), 2.24 (s, 3H).

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Example 100 Acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 5-thiophen-3-yl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 3-oxo-3-thiophene-3-yl-propionic,  ethyl ester instead of ethyl acetoacetate and 4-trifluoromethylhydrazine instead of 3,4-dimethylhydrazine, the compound of the title in the form of a solid (2.7 g, 67%). 1 H NMR (300 MHz, DMSO-d_ {6})? 8.08 (d, J = 8.5 Hz, 2H), 7.88 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 7.54 (d, J = 5.0 Hz, 1H), 5.78 (s, 1H).

b) Acid 3 '- (N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 5-thiophen-3-yl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.025 g, 13%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.9 (s at, 1H), 9.8 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.29 (d, J = 8.5 Hz, 2H), 8.15 (s, 1H), 7.8 (m, 7H), 7.6 (t, J = 7.8 Hz, 1H), 7.12 (m, 2H). MS (ES) m / z 551 (M + H) +.

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Example 101 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-methylsulfanylmethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl-3-carboxylic acid to) 5-Methylsulfanyl-2- (4-trifluoromethylphenyl) -2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that acid was used 4-methylsulfanyl-3-oxo-butyric acid,  ethyl ester instead of ethyl acetoacetate and 4-trifluoromethylphenylhydrazine instead of 3,4-dimethylphenylhydrazine, the compound was prepared of the title in the form of a solid (0.9 g, 21%). 1 H NMR (300 MHz, DMSO-d_ {6})? 8.02 (d, J = 8.6 Hz, 2H), 7.8 (d, J = 8.6 Hz, 2H), 5.49 (s, 1H), 3.5 (s, 2H), 2.05 (s, 3H).

b) Acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-methylsulfanylmethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 5-Methylsulfanyl-2- (4-trifluoromethylphenyl) -2,4-di-hydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.065 g, 35%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s at, 1H), 9.8 (s, 1H), 8.19 (s, 1H), 8.15 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 7.5 Hz, 1H), 7.84 (m, 3H), 7.8 (d, J = 7.5 Hz, 1H), 7.75 (t, J = 7.4 Hz, 1H), 7.22 (m, 2H), 3.9 (s, 2H), 2.23 (s, 3H). MS (ES) m / z 529 (M + H) +.

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Example 102 N- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -il)  methanesulfonamide to) N- (3'-nitro-2'-hydroxybiphenyl-3-yl) -methanesulfonamide

It was treated 3'-amino-3-nitrobiphenyl-2-ol (0.37 g, 1.62 mmol) in chloroform (10 ml) with methylsulfonic chloride  (2.4 mmol). After stirring at room temperature for 18 hours, the reaction mixture was added water. The phases separated and the organic phase was dried and concentrated. The resulting gum is dissolved in THF, 10% sodium hydroxy was added and heated to reflux for 18 hours. The precipitate was collected and washed with ether, giving the title compound as a colored solid yellow (0.45 g, 90%). MS (ES) m / z 309 (M + H) +.

b) N- (3'-amino-2'-hydroxybiphenyl-3-yl) -methanesulfonamide

Following the procedure in example 3d), with the exception that it was used N- (3'-nitro-2'-hydroxybiphenyl-3-yl) -methanesulfonamide  instead of acid 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as a solid. MS m / z 279 (M + H) +.

C) N- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -il)  methanesulfonamide

Following the procedure of example 1e), with the exception that it was used N- (3'-amino-2'-hydroxybiphenyl-3-yl) -methanesulfonamide  instead of the compound of example 1c), the compound of the title in the form of a solid (0.053 g, 13%). MS (ES) m / z 492 (M + H) +.

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Example 103 Acid 3 '- [N' - (1-benzo [1,3] dioxol-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene) hydrazino} -2'-hydroxybiphenyl-3- carboxylic to) 2-benzo [1,3] dioxol-5-yl-5-methyl-2,4-dihydropyrazol-3-one

Aqueous sodium nitrite was slowly added (0.69 g, 10 mmol) to a stirred solution of [1,3] dioxol-5-phenylalanine (1.27 g, 10 mmol) in aqueous HCl (0.5 ml) at -10 ° C at  -20 ° C for 20 min. Then, a quick addition was added.  tin chloride solution in aqueous HCl. After 30 min. to  -20 ° C, the solid was collected and washed with ether diethyl to produce a raw product.

Following the procedure of example 1d), with the exception that the previous raw product was used instead of 3,4-dimethylphenyl hydrazine, se prepared the title compound as a solid (0.035 g, 8%).  1 H NMR (300 MHz, DMSO-d 6) δ 7.38 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.8 (d, J = 8.4 Hz, 1H), 5.97 (s, 2H), 3.46 (s, 2H), 2.2 (s, 3H).

b) acid 3 '- [N' - (1-benzo [1,3] dioxol-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene) hydrazino] -2'-hydroxybiphenyl-3-carboxylic

Following the procedure of example 1e), with the exception that it was used 2-benzo [1,3] dioxol-5-yl-5-methyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.051 g, 66%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.9 (s a, 1H), 13.1 (s a, 1H), 9.8 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.73 (m, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.17 (m, 2H), 7.0 (d, J = 8.5 Hz, 1H), 6.07 (s, 2H), 2.33 (s, 3H). MS (ES) m / z 458 (M + H) +.

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Example 104 Acid 3 '- {N' - [1- (3,5-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (3,5-dimethylphenyl) -5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1d), with the exception that 3,5-dimethylphenylhydrazine was used instead of 3,4-dimethylphenylhydrazine, the title compound as a solid (2.62 g, 52%). 1 H NMR (300 MHz, CDCl 3) δ 7.46 (s, 2H), 6.8 (s, 1H), 3.4 (s, 2H), 2.33 (s, 6H), 2.18 (s, 3H).

b) Acid 3 '- {N' - [1- (3,5-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,5-dimethylphenyl) -5-methyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.22 g, 50%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 13.1 (s a, 1H), 9.7 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.72 (dd, J = 1.9 Hz and 6.8 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.58 (s, 2H), 7.17 7 (m, 2H), 7.0 (d, J = 8.5 Hz, 1H), 6.87 (s, 1H), 2.33 (s, 9H). MS (ES) m / z 443 (M + H) +.

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Reference Example 105

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -4'-hydroxybiphenyl-4-carboxylic acid a) Acid 3'-nitro-4'-hydroxybiphenyl-4-carboxylic

Following the procedure of example 7c), with the exception that acid was used 4'-hydroxybiphenyl-4-carboxylic  instead of acid 6- (5-Chloro-2-hydroxyphenyl) -pyridine-2-carboxylic acid, the title compound was prepared as a solid (1 g, 84%) MS (ES) m / z 260 (M + H) +.

b) Acid 3'-amino-4'-hydroxybiphenyl-4-carboxylic

Following the procedure of example 3e) with the exception that acid was used 3'-nitro-4'-hydroxybiphenyl-4-carboxylic  instead of acid 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as a solid (0.88 g, 40%) MS (ES) m / z 230 (M + H) +.

c) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -4'-hydroxybiphenyl-4-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-4'-hydroxybiphenyl-4-carboxylic  instead of the compound of example 1c), the compound of the title in the form of a solid (0.067 g, 74%). MS (ES) m / z 443 (M + H) +.

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Example 106 Acid 3 '- {N' - [1- (3-Chloro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 2- (3-Chloro-4-methylphenyl) -5-methyl-2,4-dihydropyrazol-3-one

Following the procedure of example 1 d), with the exception that it was used 3-chloro-4-methylphenylhydrazine  instead of 3,4-dimethylphenylhydrazine, the title compound as a solid (3.5 g, 63%). 1 H NMR (300 MHz, DMSO-d 6) δ 7.84 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 5.29 (s at, 2H), 2.33 (s, 3H), 2.16 (s, 3H).

b) Acid 3 '- {N' - [1- (3-Chloro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that it was used 2- (3,5-dimethylphenyl) -5-methyl-2,4-dihydropyrazol-3-one  instead of the compound of example 1d) and acid 3'-amino-2'-hydroxybiphenyl-3-carboxylic instead of the compound of example 1c), the compound of the title in the form of a solid (0.22 g, 47%). 1 H NMR (300 MHz, d_ {6} -DMSO) δ 13.7 (s a, 1H), 13.1 (s a, 1H), 9.7 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.97 (d, J = 7.1 Hz, 1H), 7.79 (m, 2H), 7.7 (d, J = 7.1 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.19 (m, 2H), 2.23 (s, 6H). MS m / z 463 (M + H) +.

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Reference Example 107

Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -4'-hydroxybiphenyl-3-carboxylic acid a) Acid 3'-amino-4'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 7c), with the exception that acid was used 3'-nitro-4'-methoxybiphenyl-3-carboxylic  instead of acid 6- (5-Chloro-2-hydroxyphenyl) -pyridine-2-carboxylic acid, the crude product was isolated.

Following the procedure in example 3d), with the exception that the previous raw product was used instead of acid 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as a solid. 1 H NMR (300 MHz, DMSO-d 6) δ 8.1 (s, 1H), 7.9 (d, J = 7.7 Hz, 1H), 7.8 (d, J = 7.7 Hz, 1H), 7.56 (m, 3H), 7.06 (d, J = 7.8 Hz, 1H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -4'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that acid was used 3'-amino-4'-hydroxybiphenyl-3-carboxylic acid  instead of the compound of example 1c), the compound of the title in the form of a solid (0.05 g, 63%). MS (ES) m / z 443 (M + H).

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Example 108 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-phosphonic a) Tetrafluoroborate 3-Bromobenzenediazone

3-Bromoaniline (17.2 was added g; 0.1 mol) to a solution of lithium tetrafluoroborate (12.0 g; 0.128 mol) in conc. Hydrochloric acid (20.0 ml) and water (80.0 ml) and The resulting suspension was cooled to 5 ° C and treated dropwise with a solution of sodium nitrite (6.9 g; 0.1 mol) in water (20.0 ml). The mixture was stirred at 5 ° C for 1 h, then filtered and the precipitate was washed with cold water (20.0 ml), cold methanol (2 x 20.0 ml) and diethyl ether (3 x 20.0 ml), giving the title compound (25.1 g; 93%).

b) Acid (3-bromophenyl) phosphonic

A suspension of the compound of Example 109a) (25.0 g; 0.093 mol) in ethyl acetate (140 ml) was treated with phosphorus trichloride (8.2 ml; 0.094 mol) followed by copper (I) (2.07 g; 0.014 mol). The mixture was heated to start the reaction (gas evolution) and then allowed to stir to room temperature (refrigeration was applied with an ice bath when it was necessary to avoid excessive exotherm) and then, when gas evolution ceased, it was stirred and heated to 50 ° C for 40 min more. After a period of cooling, it water (30.0 ml) was slowly added and the reaction volume was reduced to ~ 50 ml by evaporation. The solid precipitate is removed and then treated with ac sodium hydroxide. 10% (100 ml) and  filtered to remove insoluble material. The filtrate is acidified to pH 4 with conc. hydrochloric acid. and then left to room temperature overnight, filtered and solid crystallized from hydrochloric acid ac. 6 M (60 ml), producing the title compound (5.21 g; 24%) in the form of a colorless solid. m.p. 144-149 ° C.

c) Acid (5'-Chloro-2'-methoxybiphenyl-3-yl) phosphonic

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and the compound of Example 108b) instead of the compound of 1a), was prepared the title compound (0.95 g; 76%) in the form of a colored powder White. MS (ES) m / z 299 [M + H].

d) Acid (5'-Chloro-2'-hydroxybiphenyl-3-yl) -phosphonic

Following the procedure in example 3d), with the exception that the compound of Example 108c) was used instead of the compound of example 3c), the title compound was prepared in form of a solid (0.83 g; 90%). MS (ES) m / z 285 [M + H].

e) Acid (5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-yl) phosphonic

Following the procedure of Example 7c), with the exception that the compound of 108d) was used instead of compound of 7c), the title compound was prepared (0.76 g; 69%). MS (ES) m / z 330 [M + H].

f) Acid (3'-amino-2'-hydroxybiphenyl-3-yl) phosphonic, hydrochloride salt

Following the procedure of example 3e) with the exception that the compound of Example 108e) was used instead of acid 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as a solid (0.33 g, 88%) MS (ES) m / z 266 (M + H).

g) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-phosphonic

Following the procedure of example 1e), with the exception that the compound of Example 108f) was used instead of the compound of example 1c), the title compound as was obtained a red solid (0.092 g, 18%). 1 H NMR (300 MHz, DMSO-d_ {6}) δ 13.8 (s a, 1H), 10.5-9.5 (s a, 1H), 7.89-7.53 (m, 7H), 7.23-7.10 (m, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3 H).

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Example 109 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,4-dicarboxylic acid a) Acid 5'-Chloro-2'-methoxy-biphenyl-3,4-dicarboxylic acid

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 4-bromophthalic acid instead of the compound of 1a), it prepared the title compound (4.5 g; 82%) as a powder White color. MS (ES) m / z 307 [M + H].

b) Acid 5'-Chloro-2'-hydroxy-biphenyl-3,4-dicarboxylic acid

Following the procedure in example 3d), with the exception that the compound of Example 109a) was used instead of the compound of example 3c), the title compound was prepared in form of a solid (4.2 g; 98%). MS (ES) m / z 293 [M + H].

c) Acid 5'-Chloro-2'-hydroxy-3'-nitro-biphenyl-3,4-dicarboxylic acid

Following the procedure of Example 7c), with the exception that the compound of 109b) was used instead of compound of 7c), the title compound was prepared (4.7 g; 98%). MS (ES) m / z 338 [M + H].

d) Acid 3'-amino-2'-hydroxy-biphenyl-3,4-dicarboxylic acid, hydrochloride salt

Following the procedure of example 3e) with the exception that the compound of Example 109c) was used instead of acid 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as a solid (4.1 g, 99%) MS (ES) m / z 274 (M + H).

e) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,4-dicarboxylic acid

Following the procedure of example 1e), with the exception that the compound of Example 109d) was used instead of the compound of example 1c), the title compound as was obtained a red solid (0.05 g, 63%). Anal. (C 26 H 22 N 4 O 6 {0.75 H 2 O) calc .: C, 62.46; H, 4.74; N, 11.21, found: C, 62.63; H, 4.86; N, 10.84.

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Example 110 Acid 2 ', 6-dihydroxy-3' - {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} biphenyl-3-carboxylic acid a) Acid 5'-Chloro-4-hydroxy-2'-methoxy-biphenyl-3-carboxylic acid

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used acid 5-Bromo-2-hydroxybenzoic instead of the compound of 1a), the title compound was prepared (4.5 g; 70%) in the form of a white powder. MS (ES) m / z 279 [M + H].

b) Acid 5'-Chloro-4,2'-dihydroxy-biphenyl-3-carboxylic acid

Following the procedure in example 3d), with the exception that the compound of Example 110a) was used instead of the compound of example 3c), the title compound was prepared in form of a solid (2.9 g; 69%). MS (ES) m / z 265 [M + H].

c) Acid 5'-Chloro-4,2'-dihydroxy-3'-nitrobiphenyl-3-carboxylic acid

Following the procedure of Example 7c), with the exception that the compound of 110b) was used instead of compound of 7c), the title compound was prepared. MS (ES) m / z 310 [M + H].

d) Acid 3'-amino-4,2'-dihydroxy-biphenyl-3-carboxylic acid, hydrochloride salt

Following the procedure of example 3e) with the exception that the compound of Example 110c) was used instead of acid 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as a solid (0.9 g, 37%) MS (ES) m / z 246 (M + H).

e) Acid 2 ', 6-dihydroxy-3' - {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} biphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that the compound of Example 110d) was used instead of the compound of example 1c), the title compound was obtained in Shape of a solid red. Anal. (C 25 H 22 N 4 O 5 {0.5 H 2 O) calc .: C, 64.23; H, 4.96; N, 11.98, found: C, 64.37; H, 4.97; N, 11.85.

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Example 111 Acid 4-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- carboxylic a) Acid 2- (5-Chloro-2-methoxyphenyl) isonicotinic

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 2-Chloroisonicotinic acid instead of the compound of 1a), the title compound was prepared in the form of a powder of Gray color (2.3 g; 87%) as a white powder. MS (ES) m / z 264 [M + H].

b) Acid 2- (5-Chloro-2-hydroxyphenyl) isonicotinic

Following the procedure in example 3d), with the exception that the compound of Example 111a) was used instead of the compound of example 3c), the title compound was prepared in form of a solid (1.55 g; 82%). MS (ES) m / z 250 [M + H].

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c) Acid Isonicotinic 2- (5-Chloro-2-hydroxy-3-nitrophenyl)

Following the procedure of Example 7c), with the exception that the compound of 111b) was used instead of compound of 7c), the title compound was prepared in the form of a orange powder (1.1 g; 65%). MS (ES) m / z 296 [M + H].

d) Acid 2- (3-Amino-2-hydroxyphenyl) isonicotinic, sodium salt

Following the procedure of example 3e) with the exception that the compound of Example 111c) was used instead of acid 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as a solid (0.81 g, 94%). MS (ES) m / z 246 (M + H).

e) Acid 4-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- carboxylic

Following the procedure of example 1e), with the exception that the compound of Example 111d) was used instead of the compound of example 1c), the title compound as was obtained a red solid (0.19 g; 43%). 1 H NMR (300 MHz, DMSO-d_ {6} δ 13.8 (s a, 1H), 8.74 (d, J = 4.9 Hz, 1H), 8.53 (s, 1H), 7.97 (m, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.78-7.64 (m, 3H), 7.21 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H).

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Example 112 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid to) 1- (3,4-dimethylphenyl) -1,2-dihydropyrazol-3-one

A hydrochloride suspension of 3,4-dimethylphenylhydrazine (2.0 g; 0.012 mol) and potassium carbonate (3.2 g; 0.023 mol) in anhydrous ethanol (40.0 ml) was treated dropwise with diethyl (ethoxymethylene) malonate (2.5 g; 0.012 mol) and the mixture was stirred and heated to reflux for 3 h. After cooling the mixture was evaporated and the residue it was suspended in water and acidified to pH 2 followed by extraction with ethyl acetate. After drying and evaporation, the acid resulting intermediate 1- (3,4-dimethyl-phenyl) -3-oxo-2,3-dihydro-1H-pyrazol-4-carboxylic acid,  ethyl ester was dissolved in methanol (10.0 ml) and sodium hydroxide 10% aqueous (10.0 ml), stirred at room temperature for 3 h and then heated to reflux to perform hydrolysis. The solution was cooled, acidified to pH 4 with aq. hydrochloric acid. 3 M and stirred at room temperature for 2 h to perform the decarboxylation The mixture was extracted with ethyl acetate, dried and evaporated, giving the title compound (87%) as a solid yellow. 1 H NMR (300 MHz, CDCl 3) δ 7.61 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.2 and 2.3 Hz, 1H), 7.48 (t, J = 1.3 Hz, 1H), 1.16 (d, J = 8.2 Hz, 1H), 3.50 (d, J = 1.3 Hz, 2H).

b) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid

Following the procedure of example 1e), with the exception that the compound of Example 112d) was used instead of the compound of example 1c), the title compound was obtained in Red needle shape. m.p. 226-228 ° C (ethanol). 1 H NMR (300 MHz, DMSO-d 6) δ 8.20 (s, 1H), 8.14 (s, 1H), 7.97 (m, 1H), 7.81 (m, 1H), 7.73-7.61 (m, 4H), 7.26-7.13 (m, 3H), 2.29 (s, 3H), 2.25 (s, 3H). Anal. (C 24 H 20 N 4 O 4 {1.0 CH 3 CH 2 OH) calc .: C, 65.87; H, 5.52; N, 11.81, found: C, 65.17; H, 5.73; N, 11.58.

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Example 113 Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-sulfonic acid a) Acid 5'-Chloro-2'-methoxybiphenyl-3-sulfonic

Following the procedure of Example 1b), with the exception that acid was used 2-methoxy-5-chlorophenylboronic  instead of 4-carboxyphenylboronic acid, and was used 3-Bromobenzenesulfonic acid instead of the compound of 1a), the title compound (0.41 g) was prepared as a white powder MS (ES) m / z 299 [M + H].

b) Acid 5'-chloro-2'-hydroxybiphenyl-3-sulfonic

Following the procedure in example 3d), with the exception that the compound of Example 113a) was used instead of the compound of example 3c), the title compound was prepared in form of a solid (0.87 g; 99%). MS (ES) m / z 285 [M + H].

c) Acid 5'-Chloro-2'-methoxy-3'-nitrobiphenyl-3-sulfonic

Following the procedure of Example 7c), with the exception that the compound of 113b) was used instead of compound of 7c), the title compound was prepared in the form of a solid yellow. MS (ES) m / z 330 [M + H] used directly in the next stage without further purification.

d) Acid 3'-amino-2'-hydroxybiphenyl-3-sulfonic

Following the procedure of example 3e) with the exception that the compound of Example 113c) was used instead of acid 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid, the title compound was prepared as an EM solid (EN) m / z 266 (M + H) used directly in the next stage without additional purification

e) Acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-sulfonic acid

Following the procedure of example 1e), with the exception that the compound of Example 110d) was used instead of the compound of example 1c), the title compound as was obtained a red solid (0.01 g). MS (ES) m / z 479 (M + H).

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Example 114 5- (3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-yl -methylene) thiazolidine-2,4-dione to) 3-Methoxy-4'-nitrobiphenyl-4-carbaldehyde

A solution of 1-bromo-2-methoxy-3-nitrobenzene (2.30 g; 9.9 mmol) in 1,4-dioxane (80.0 ml) was treated with tetrakis (triphenylphosphine) palladium (0) (0 , 15 g). After 2 min, 3-formylbenzeneboronic acid (1.48 g; 9.9 mmol) was added followed by aq sodium carbonate. 2M (9.9 ml; 19.8 mmol). The reaction mixture was stirred and heated at reflux for 18 h. The reaction was cooled to room temperature and partitioned between ethyl acetate and 3M aqueous hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x). The combined organic phases were washed with brine, dried and evaporated and the residue was purified by chromatography (silica gel, 5% ethyl acetate / hexanes), to give the title compound (1.62 g; 63%) in the form of a yellow oil. MS (ES +) m / e 258 [M + H] +.

b) 5- (2'-Methoxy-3'-nitrobiphenyl-3-ylmethylene) thiazolidine-2,4-dione

A solution of 3-methoxy-4'-nitrobiphenyl-4-carbaldehyde in (1.62 g; 6.3 mmol) in ethanol (35.0 ml) was treated with 2,4-thiazolidinedione (738 mg; 6.3 mmol) and then with piperidine (100 µl). The mixture was stirred and heated to reflux. for 12 h. More amount of 4-thiazolidinedione (370 mg; 3.1 mmol) and the reaction stirred and heated to reflux for 1 h more with the formation of a yellow precipitate. The reaction was cooled to room temperature, filtered and the precipitate was washed with ethanol, giving the title compound (880 mg; 40%) as a solid yellow.

C) 5- (2'-Hydroxy-3'-nitro-biphenyl-3-ylmethylene) thiazolidine-2,4-dione

A solution of 5- (2'-Methoxy-3'-nitrobiphenyl-3-ylmethylene) thiazolidine-2,4-dione (875 mg; 2.45 mmol) in glacial acetic acid (25.0 ml) was treated with a 48% aqueous solution of hydrobromic acid (25.0 ml) and the The solution was stirred and heated at reflux for 12 h. The reaction cooled to room temperature and filtered, giving 400 mg (48%) of 5- (2'-hydroxy-3'-nitro-biphenyl-3-ylmethylene) -thiazolidine-2,4-dione in the form of a bright yellow solid.

d) 5- (3'-Amino-2'-hydroxybiphenyl-3-ylmethylene) thiazolidine-2,4-dione

To a solution of 5- (2'-hydroxy-3'-nitrobiphenyl-3-ylmethylene) thiazolidine-2,4-dione in (400 mg; 1.17 mmol) in concentrated hydrochloric acid (20.0 ml) tin dichloride (640 mg; 3.36 mmol) was added and the mixture was stirred and heated at reflux for 12 h. The reaction is cooled to room temperature, filtered and the precipitate is washed with water, giving a solid that was purified by chromatography (ODS-silica, gradient elution, [acetonitrile al 10-90% / water (0.1% TFA)], giving the compound of titer (120 mg; 33%) in the form of an orange solid. EM (EN +) m / e 313 [M + H] '.

e) 5- (3 '- { N ' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl -3-yl-methylene) thiazolidine-2,4-dione

Following the procedure of Example I (e) with the exception that the compound of Example 114 (d) was used instead of the compound of Example 1 (c), the title compound (52 mg; 100%) in the form of a colored solid brown. MS (ES +) m / e 526 [M + H] +.

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Example 115 Capsule Composition

An oral dosage form to administer a TPO receptor agonist of the present invention by filling a conventional two-piece hard gelatin capsule with the ingredients in the proportions shown in Table I, a continuation.

TABLE I

fifteen

Example 116 Parenteral Injectable Composition

An injectable way to administer a TPO receptor agonist of the present invention occurs stirring 1.5% by weight of acid 4 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-3-carboxylic acid  (Compound of Example 2) in 10% by volume propylene glycol in Water.

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Example 117 Tablets Composition

Sucrose, calcium sulfate dihydrate and a TPO receptor agonist of the present invention, as shown in Table II below, they are mixed and granulated in the proportions shown with a 10% solution of. Granules moist are screened, dried, mixed with starch, talc and stearic acid; they are sifted and pressed giving a compressed.

TABLE II

16

Among the compounds of the present invention, the following are prepared;

acid 3 '- {N' - [3-cyclopropyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

acid 3 '- {N' - [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

acid 3 '- {N' - [1- (3-Chloro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -5'-fluoro-2'-hydroxybiphenyl-3 -carboxylic;

acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3-Aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5 acid -carboxylic;

acid 3 '- {N' - [3-methyl-1- (4-methylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3,5-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

(3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-biphenyl) -1 , 1,1, -trifluoromethanesulfonamide;  Y

acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid.

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Among the compounds of the invention are they particularly prefer the following;

acid 3 '- {N' - [3-cyclopropyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-a-carboxylic acid;

acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

acid 3 '- {N' - [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

acid 3 '- {N' - [1- (3-Chloro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino) -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -5'-fluoro-2'-hydroxybiphenyl-3 -carboxylic;

acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3-Aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5 acid -carboxylic; Y

acid 3 '- {N' - [3-methyl-1- (4-methylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid.

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Among the compounds of the invention are they particularly prefer the following;

acid 3 '- {N' - [3-cyclopropyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ;

acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino) -2'-hydroxybiphenyl-3-carboxylic acid;

acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;  Y

3- {N '- [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl .

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The most preferred among the compounds of the invention is,

acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid.

Acid compound 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid  showed an activity of EC 50 = 0.03 uM, 100% TPO in the previous proliferation test.

Although the preferred embodiments of the invention are illustrated above, it should be appreciated that the invention is not limited to the precise instructions described in the present document and that reserves the right to any modification that is within the scope of the following claims.

Claims (25)

1. A compound that has the Formula (VI):

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17

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in the that:

quad

R is a substituted aryl; and R1 is hydrogen;

or:

quad

R is hydrogen; and R1 is an aryl replaced;

and in any case:

quad

R 2 and R 3 are each selected independently between hydrogen, alkyl C 1-6, C 1-6 alkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphic acid and acid sulfonic;

quad

R 15 is selected from the constituted group by alkyl, substituted alkyl, aryl C 1 -C 12, alkoxy and halogen;

quad

m is 0-4; and

quad

And it is selected from:

phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl are optionally substituted with one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, aryl C 1 -C 12 substituted, alkoxy and halogen;

quad

and where:

by the term "aryl", as used in this document, a cyclic or polycyclic aromatic ring is understood containing 1 to 14 carbon atoms and containing optionally one to five heteroatoms, with the proviso that when the number of carbon atoms is 1 the aromatic ring contain at least four heteroatoms, when the number of atoms carbon be 2 the aromatic ring contains at least three heteroatoms, when the number of carbons is 3 the ring aromatic contain at least two heteroatoms and when the number of carbon atoms be 4 the aromatic ring contains at least one heteroatom; by the term "aryl C_ {1} -C_ {12} ", as used in this document, it is understood phenyl, naphthalene, 3,4-Methylenedioxyphenyl, pyridine, biphenyl, quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole or tetrazole; Y by the term "substituted", as used in This document, it is understood that the subject chemical moiety has one or more substituents selected from the group consisting of:

-CO 2 R 20, aryl, -C (O) NHS (O) 2 R 20, -NHS (O) 2 R 20, hydroxyalkyl, alkoxy, -C (O) NR 21 R 22, acyloxy, alkyl, amino, N-acylamino, hydroxy, - (CH 2) g C (O) OR 8, -S (O) n R 8, nitro, tetrazol, cyano, oxo, halogen, and trifluoromethyl, where g is 0-6, R 8 is hydrogen or alkyl, R20 is selected from hydrogen, C 1 -C 4 alkyl, aryl and trifluoromethyl, and R 21 and R 22 are independently selected from hydrogen, C1-C4 alkyl, aryl and trifluoromethyl, and n is 0-2;

and pharmaceutically active salts, hydrates and solvates Acceptable of it.

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2. A compound of Formula VI according to the claim 1, wherein:

quad

R is a C 1 -C 12 aryl replaced; Y

quad

R1 is hydrogen;

quad

each of R2 and R3 is selected independently between hydrogen, alkyl C 1-6, C 1-6 alkoxy, nitro, cyano, halogen, substituted alkyl and cycloalkyl;

quad

R 15 is selected from the constituted group by alkyl, substituted alkyl, aryl C 1 -C 12, alkoxy and halogen;

quad

m is 0-2; and

quad

And you select between,

phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl are optionally substituted with one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, aryl C 1 -C 12 substituted, alkoxy and halogen;

and pharmaceutically active salts, hydrates and solvates Acceptable of it.

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3. A compound of Formula VI according to the claim 1, wherein:

quad

R is a C 1 -C 12 aryl replaced; Y

quad

R1 is hydrogen;

quad

each of R2 and R3 is selected independently between hydrogen, alkyl C 1-6, substituted alkyl and halogen;

quad

R 15 is selected from the constituted group by C 1-4 alkyl, alkoxy C 1-4, aryl C 1 -C 12 and halogen;

quad

m is 0; and

quad

And it is selected from:

phenyl, pyridinyl and pyrimidinyl, where phenyl, pyridinyl and pyrimidinyl is optionally substituted with one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, aryl C 1 -C 12 substituted, alkoxy and halogen;

and pharmaceutically active salts, hydrates and solvates Acceptable of it.

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4. A compound of Formula VI according to the claim 1, 2 or 3, wherein:

quad

by the term "substituted", as used in This document, unless otherwise indicated, means that the subject chemical moiety has a substituent selected from the group consisting of:

-CO 2 R 20, aryl, -C (O) NHS (O) 2 R 20, -NHS (O) 2 R 20, hydroxyalkyl, alkoxy, -C (O) NR 21 R 22, acyloxy, alkyl, amino, N-acylamino, hydroxy, - (CH 2) g C (O) OR 8, -S (O) n R 8, nitro, tetrazol, cyano, oxo, halogen and trifluoromethyl, where g is 0, R 8 is hydrogen or alkyl, R20 is selected from hydrogen, alkyl C 1 -C 4, aryl and trifluoromethyl, and R 21 and R22 are independently selected from hydrogen, C 1 -C 4 alkyl, aryl and trifluoromethyl, and n is 0-2.

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5. A compound of Formula VI according to the claim 1, 2, 3 or 4, wherein:

quad

by the term "alkoxy", as used herein document, it is understood -OCH_ {3} or -OC (CH 3) 2 CH 3;

quad

by the term "cycloalkyl" or "cycloalkyl substituted ", as used herein, is understands:

cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl-4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl, cyclopropyl or cyclopentyl;

quad

by the term "acyloxy", as used herein document, it is understood -OC (O) CH 3, -OC (O) CH (CH 3) 2 or -OC (O) (CH 2) 3 CH 3;

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quad

by the term "N-acylamino", as used in this document, it is understood -N (H) C (O) CH 3, -N (H) C (O) CH (CH 3) 2  or -N (H) C (O) (CH 2) 3 CH 3;

quad

by the term "aryloxy", as used herein document, is understood as phenoxy, 4-fluorophenyloxy or biphenyloxy; Y

quad

an alkyl substituent is: -CH 3, -CH_ {2} -CH_ {3}, -CH_ {2} -CH_ {2} -CH_ {3}, -CH (CH 3) 2, -C (CH 3) 3, - (CH 2) 3 -CH 3, -CH 2 -CH (CH 3) 2 or -CH (CH 3) - CH 2 -CH 3.

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6. A compound according to claim 1 selected from: acid 4 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-4-carboxylic acid; acid 4 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -3'-hydroxybiphenyl-3-carboxylic acid; 3 '- {N' - [1- (4- tert- Butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 2-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -5'-chloro-2 acid '-hydroxybiphenyl-3-carboxylic acid; 2-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic; 3-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5 acid -carboxylic; acid 2-aza-5'-chloro-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2 ' -hydroxybiphenyl-3-carboxylic acid; 2-aza-3 '- {N' - [1- (4- tert- butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 acid '-methylbiphenyl-3-carboxylic acid; acid 2-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 ' -methylbiphenyl-3-carboxylic acid; 3 '- {N' - [1- (4- tert- Butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5'-methylbiphenyl- 3-carboxylic; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -5'-fluoro-2'-hydroxybiphenyl-3 -carboxylic; acid 7 - ({N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxyphenyl) quinolin-4 [1H] - one-3-carboxylic; 7 - ({N '- [1- (4- tert- Butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxyphenyl) quinolin-4 [1H] acid -one-3-carboxylic; acid 3-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- carboxylic; acid 3-aza-3 '- (N' - [1- {3-methyl- [4- (1-methyl ethyl) phenyl] -5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino) -2'- hydroxybiphenyl-5-carboxylic; 3-aza-3 '- {N' - [1- (4- tert- butylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5- carboxylic; acid 5'-chloro-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl -3-carboxylic; acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3,5-dioxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (2-Ethoxy-2-oxoethyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-4' - (tetrazol-5- il) biphenyl; 3 '- (N' - {1- [2- (N- tert- butyl) amino-2-oxoethyl] -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene} hydrazino) -2 '-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-Chloro-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 5-chloro-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-4' - ( tetrazol-5-yl) biphenyl; acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,5-dicarboxylic acid; acid 3-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-5 ' -methylbiphenyl-5-carboxylic acid; acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-4-carboxylic acid; acid 3 '- {N' - [1- (3,4-Dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (4-methoxyphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; (3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-biphenyl) -1 , 1,1-trifluoromethanesulfonamide; acid 3 '- {N' - [1- (3,4-Dichlorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-methyl-5-oxo-1- (3-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 8- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} quinolin-4 [1 H] -one-3-carboxylic acid; acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-methyl-5-oxo-1- (4-N-methylcarboxamidolfenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; N- [1- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-yl) methanoyl] methanesulfonamide; acid 3 '- {N' - [3-methyl-5-oxo-1-phenyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-methyl-1- (4-methylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (4-chlorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethoxy) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl- 3-carboxylic; 3 '- {N' - [3- tert- Butyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid ; acid 3 '- {N' - [3-methyl-1- (4-methyl-2,3,5,6-tetrafluorophenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'- hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-phenyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 3- {N '- [1- (3,4-dimethylphenyl) -5-oxo-3-phenyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ; 3- {N '- [1- (3,4-dimethylphenyl) -3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ; 3- {N '- [1- (3,4-dimethylphenyl) -3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ; 3- {N '- [1- (3,4-dimethylphenyl) -3- (1-methylethoxy) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl; 3- {N '- [1- (4-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3- {N '- [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5 -ylbiphenyl; 3- {N '- [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic; 3- {N '- [1- (3,4-dimethylphenyl) -3-pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl; 3- {N '- [1- (3,4-dimethylphenyl) -3-pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino } -2-hydroxy-3'-tetrazol-5-ylbiphenyl; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -carboxylic; 3- {N '- [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5 -ylbiphenyl; acid 3 '- {N' - [1- (3-Fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylpyrimidin-2-yl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl-3- carboxylic; 3'-N- tert- butoxycarbonylamino-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxybiphenyl ; 3'-amino-3- {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxybiphenyl; 3- {N '- [1- (3-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl; acid 3 '- {N' - [1- (3-fluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 3- {N '- [3-methyl-5-oxo-1- (2,3,4,5,6-pentafluorophenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3' -tetrazol-5-ylbiphenyl; acid 3 '- {N' - [3-methyl-5-oxo-1- (2,3,4,5,6-pentafluorophenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl- 3-carboxylic; acid 3 '- {N' - [1- (3,4-Difluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 3- {N '- [1- (3,4-dimethylphenyl) -3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ; 3- {N '- [1- (3,4-Difluorophenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino } -2-hydroxy-3'-tetrazol-5-ylbiphenyl; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-trifluoromethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -6-fluoro-2'-hydroxybiphenyl-3- carboxylic; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 3- {N '- [1- (3,4-dimethylphenyl) -5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methyl-1 H -pyrrole-3-yl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 3- {N '- [1- (3,4-dimethylphenyl) -3- (1-methyl-1H-pyrrol-3-yl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} - 2-hydroxy-3'-tetrazol-5-ylbiphenyl; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic; 3- {N '- [1- (3,4-dimethylphenyl) -3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol -5-ilbiphenyl; N- (2'-hydroxy-3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethyl-phenyl) -1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl- 3-yl) -1,1,1-trifluoromethanesulfonamide; N- (2'-hydroxy-3 '- {N' - [1- (3-fluoro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl-3-yl) -1,1,1-trifluoromethanesulfonamide; N- (2'-hydroxy-3 '- {N' - [1- (4-fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl-3-yl) -1,1,1-trifluoromethanesulfonamide; N- (2'-hydroxy-3 '- {N' - [1- (3,4-difluorophenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} biphenyl- 3-yl) -1,1,1-trifluoromethanesulfonamide; N- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-yl ) guanidine; acid 3'-N '- [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; 3- {N '- [1- (3,4-dimethylphenyl) -3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2-hydroxy-3'-tetrazol-5-ylbiphenyl ; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thien-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic; acid 3 '- {N' - [3-cyclopropyl-1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiazol-2-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3- (1-methylethyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic; acid 3 '- {N' - [3- (benzyloxymethyl) -1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-ethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-hydroxymethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [3-benzyloxymethyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methylsulfanylmethyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3- carboxylic; acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-thiophene-3-yl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxy-biphenyl-3- carboxylic; acid 3 '- {N' - [5-oxo-1- (4-trifluoromethylphenyl) -3-methylsulfanylmethyl-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; N- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3 -yl) methanesulfonamide; acid 3 '- [N' - (1-benzo [1,3] dioxol-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene) hydrazino] -2'-hydroxybiphenyl-3- carboxylic; acid 3 '- {N' - [1- (3,5-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3-Chloro-4-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-phosphonic; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3,4-dicarboxylic acid; acid 2 ', 6-dihydroxy-3' - {N '- [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} biphenyl-3-carboxylic acid ; acid 4-aza-3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-5-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-sulfonic acid;  Y 5- (3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-ylmethylene ) thiazolidine-2,4-dione; and pharmaceutically active salts, hydrates and solvates Acceptable of them.

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7. A drug for use in therapy, manufactured using and comprising a compound of Formula (VI) as has been defined in any one of claims 1 to 6. 8. A pharmaceutical composition comprising a compound of Formula (VI), as defined in any one of claims 1 to 6, and a pharmaceutically carrier acceptable. 9. A pharmaceutical composition for use in the improvement of platelet production in a human being that need to comprise a compound of Formula (VI), as has been defined in any one of claims 1 to 6, and a pharmaceutically acceptable vehicle,

quad

and where the composition is for administration at human being of a therapeutically effective amount of the compound of Formula (VI).

10. A pharmaceutical composition for use in the thrombocytopenia treatment comprising a compound of Formula (VI), as defined in any one of the claims 1 to 6, and a pharmaceutically carrier acceptable. 11. A pharmaceutical composition according to claim 8, 9 or 10, which is for oral administration. 12. Use of a compound of Formula (VI), as defined in any one of claims 1 to 6, in the preparation of a medicament for use in the treatment of thrombocytopenia 13. Use of a compound of Formula (VI), as defined in any one of claims 1 to 6, in the preparation of a medicament for use in improving production of platelets in a human being who needs it, and where the medicine is for the administration to the human being of an amount therapeutically effective of the compound of Formula (VI). 14. The use according to claim 12 or 13, in which medication is for oral administration. 15. A procedure to prepare a pharmaceutical composition containing a vehicle or diluent pharmaceutically acceptable and an effective amount of a compound of Formula (VI) as described in claim 1 and pharmaceutically acceptable salts, hydrates and solvates thereof, the process comprising putting the compound of the Formula (VI) together with the carrier or diluent pharmaceutically acceptable. 16. A procedure for preparing a compound of Formula (VI) as defined in any one of the claims 1 to 6, the process comprising the reaction of a compound of Formula (VII) 18 or a protected form thereof with a compound of Formula (VIII) or a tautomeric equivalent (IX) 19 in the that:

quad

R is a phenyl or pyridinyl ring substituted with one or more of the following:

-C (O) OH, tetrazole, sulfonic acid, hydroxy, methyl, fluoro, NHSO2 CF3 and C (O) NHSO 2 CH 3; and R1 is hydrogen,

or:

quad

R is hydrogen; and R1 is a phenyl ring or pyridinyl substituted with one or more of the following:

-C (O) OH, tetrazole, sulfonic acid, hydroxy, methyl, fluoro, NHSO2 CF3 and C (O) NHSO 2 CH 3;

and in any case:

quad

R 2 and R 3 are independently selected between hydrogen, C 1-6 alkyl and halogen;

quad

R 15 is selected from the constituted group by C 1-6 alkyl, alkoxy C 1-6, trifluoromethyl and halogen; and

quad

And you select between,

quad

phenyl that is optionally substituted with each other three substituents selected from the group constituted by:

quad

alkyl, substituted alkyl, trifluoromethyl and halogen; Y

followed, if necessary or desired, of salt formation

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17. A pharmaceutical composition according to claim 9, for the co-administration of a therapeutically effective amount of a selected agent among the group consisting of: colony stimulation factor, cytokine, chemokine, interleukin or receptor agonist cytokine 18. The composition according to the claim 17 wherein the agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11, SCF, Ligand FLT3, LIF, IL-3, IL-6, IL-1 or IL-5 or a biologically active derivative of any of said Agents 19. An in vitro method to enhance the stimulation of megakaryocyte maturation and / or platelet production comprising adding an effective amount of a compound as defined in claim 1 to the culture medium of cells expressing the TPO receptor . 20. An in vitro method for enhancing stimulation of megakaryocyte maturation and / or platelet production comprising adding an effective amount of a compound as defined in claim 1 to the culture medium of stem cells, marrow cells bone, cord blood cells or peripheral blood cells. 21. An in vitro procedure to enhance the survival and / or proliferation of stem cells, bone marrow cells, cord blood cells, peripheral blood cells or other types of cells expressing the TPO receptor in culture comprising culturing said cell in a medium containing an effective amount of a compound as defined in claim 1. 22. A procedure in accordance with the claim 21 further comprising the co-administration of a therapeutically amount effective of a stimulation factor of colonies, cytokines, chemokines, interleukins or a receptor agonist cytokine 23. A compound of claim 1, for Use as an immune adjuvant. 24. A compound according to the claim 23, for use as an immune adjuvant and for the administration with a vaccine and / or immunomodulator. 25. A compound according to the claim 6 which is selected from: 3 '- {N' - [1- (4- tert- Butylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid; acid 3 '- {N' - [1- (3,4-dimethylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -5'-fluoro-2'-hydroxybiphenyl-3 -carboxylic; acid 3 '- {N' - [3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid;  Y acid 3 '- {N' - [1- (4-Fluoro-3-methylphenyl) -3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene] hydrazino} -2'-hydroxybiphenyl-3-carboxylic acid.